transforming patient care through translational research in hormone receptor positive breast cancer
TRANSCRIPT
Transforming patient care through translational research in hormone receptor positive
breast cancer
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
Professor Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
170271
Disclaimer
ldquoThe statements views and opinions contained in this symposium are
those of the authors and are not endorsed by nor do they necessarily
reflect the opinions of Pfizerrdquo
ldquoThis symposium contains information on investigational products in
development from a research perspective The information aims to be
truthful accurate balanced fair and not misleading It is supported by
relevant scientific data and is non-promotionalrdquo
Agenda
The many faces of CDK46 inhibition
Erik Knudsen
10 minute introduction to the keynote presentation
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat
40 minute keynote presentation with audience questions
Audience questions and discussion
Closing remarks
Question cards are provided or please raise your hand
Remember to complete your evaluation form
The many faces of CDK46 inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
170271
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
(indexdo)Data Sets (data_setsjsp) Web API (web_apijsp) RMATLAB (cgds_rjsp) Tutorials (tutorialjsp) FAQ (faqjsp) News (newsjsp) Tools (toolsjsp) About (about_usjsp)
Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Disclaimer
ldquoThe statements views and opinions contained in this symposium are
those of the authors and are not endorsed by nor do they necessarily
reflect the opinions of Pfizerrdquo
ldquoThis symposium contains information on investigational products in
development from a research perspective The information aims to be
truthful accurate balanced fair and not misleading It is supported by
relevant scientific data and is non-promotionalrdquo
Agenda
The many faces of CDK46 inhibition
Erik Knudsen
10 minute introduction to the keynote presentation
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat
40 minute keynote presentation with audience questions
Audience questions and discussion
Closing remarks
Question cards are provided or please raise your hand
Remember to complete your evaluation form
The many faces of CDK46 inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
170271
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
(indexdo)Data Sets (data_setsjsp) Web API (web_apijsp) RMATLAB (cgds_rjsp) Tutorials (tutorialjsp) FAQ (faqjsp) News (newsjsp) Tools (toolsjsp) About (about_usjsp)
Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Agenda
The many faces of CDK46 inhibition
Erik Knudsen
10 minute introduction to the keynote presentation
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat
40 minute keynote presentation with audience questions
Audience questions and discussion
Closing remarks
Question cards are provided or please raise your hand
Remember to complete your evaluation form
The many faces of CDK46 inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
170271
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
The many faces of CDK46 inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
170271
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Erik Knudsen
University of Arizona Cancer Center
Tucson United States
The many faces of CDK46 inhibition
bull Historical perspective surrounding CDK46 inhibition
bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer
bull Key questions related to CDK46 inhibition in breast cancer
ndash Biomarkers determinants of durable response
ndash Nature of progressive disease
ndash Combination approaches to prevent progression
ndash Additional indications in breast cancer
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
1970-1990 Cell Cycle Experiments
2001 CDKCyclins
1902 Cell Division
1900 2000 1970 1990
CDKCyclins Drive the cell cycle
Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell
A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science
Complementation used to clone human cdc2 Lee 1987 Cell
Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell
An essential G1 function for cyclin-like proteins Richardson 1989 Cell
A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS
Role of CDC28 and cyclins during mitosis Surana 1991 Cell
Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell
Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS
Defining CDK in control of proliferation
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
1992-1994 Discovery of CDK46
CDK4 or CDK6
CycD
1993-1994 Cellular CDK46 Inhibitors
1991 1992 1994
A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991
Human D-type cyclin cloned by complementation Xiong 1991 Cell
Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene
Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell
CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene
Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature
1993
1991 Cloning of Cyclin D1
Cyclin D1
CSF-inducible G1 cyclin Matsushime 1991 Cell
CDK4 or CDK6
CycD
A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature
Characterisation of CDK46 Kinases cyclins inhibitors
p16INK4A
Dysregulation of Cyclin D CDK46 p16ink4a
in cancer
42017 1246 PMcBioPortal f or Cancer Genomics
Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub
Modify Query
cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)
Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars
(httpswwwbiostarsorgtcbioportal)
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Visualize Your Data (visualize_your_datajsp)
Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)
Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types
Sort alphabetically
PDF SVG
Overview Mutations Expression Download Bookmark
+ + + + + + + + + + + + + + + + + - + + + + + +
+ + + + + + + + + + + + + - + + + + + + + + + +
MP
NS
T (M
SK
CC
)
GB
M (T
CG
A)
GB
M (T
CG
A 2
013)
Head amp
neck (T
CG
A)
GB
M (T
CG
A 2
008)
Eso
phagus (T
CG
A)
Head amp
neck (T
CG
A p
ub)
Mela
nom
a (T
CG
A)
NC
I-60
Pancre
as (U
TS
W)
Bla
dder (T
CG
A)
Pancre
as (T
CG
A)
Lung sq
u (T
CG
A p
ub)
CS
CC
(DFC
I 2015)
Bla
dder (T
CG
A 2
014)
Lung sq
u (T
CG
A)
CC
LE
(Nova
rtisBro
ad 2
012)
Meso
thelio
ma (T
CG
A)
AC
bC
(MS
KC
CB
reast 2
015)
Sto
mach
(TC
GA p
ub)
Bre
ast (B
CC
RC
Xenogra
ft)
NS
CLC
(TC
GA 2
016)
LG
G-G
BM
(TC
GA 2
016)
Sto
mach
Eso
phageal
Cancer type
Mutation data
CNA data
0
10
20
30
40
50
60
70
80
Alte
ratio
n F
req
ue
ncy
Mutation Deletion Amplification Multiple alterations
126 studies ( altered samples lt 36) out of 150 have been filtered out
D1adapi CKD1a CKD1adapi CKdapi
Cas
e 3
C
ase
4
No
rma
l
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
1992 CDK46 and RB Phosphorylation
1995 Mutual Exclusivity in Cancer
1996-2001 Functions of the RB-Pathway
1992 1994 1996 1998 2000
The RB-pathway and functional interactions
RB
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature
CDK4 or CDK6
CycD
Co-repressors
RB
E2F RB
P
E2F
p16INK4A
Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev
Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell
Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc
E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc
Canonical CDK46-pathway
Role of cyclin D1 as therapeutic target Yu 2001 Nature
Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer
Mitogens
Oncogenes
Proliferation
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
1992 First CDK Inhibitors
2004 First Specific CDK46 Inhibitor
2005-2014 CDK46 Inhibitor Development
2002 2010 Present
Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther
Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med
Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer
Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res
CDK46 Inhibitors Improve PFS in
HR+HER2- breast cancer
Turner 2015 N Engl J Med
2015 Effectiveness Shown in Breast Cancer
Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst
PALOMA 2 PALOMA 3
MONALEESA 2
CDK-inhibitors Start to present
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
How did CDK46 inhibition emerge in HR+HER2- breast cancer
Many other cancer types show deregulation of CDK46
Many of these tumor types have limited effective therapies
ndash great clinical need
ndash great potential opportunity
ndash why most impactful in HR+HER2-
Witkiewicz et al Nat Comm 2015
Moore et al J Clin Oncol 2007
Excellent example of translational research impacting on
treatment of patients with breast cancer
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Luminal
(HR+) Basal
(TNBC)
ER
ER+P
D
0
20
40
60
80
Data 6
TNBC
TNBC
0
20
40
60
80
Data 8HR+ TNBC
K
i67 p
ositiv
e
DMSO PD
K
i67 p
ositiv
e
DMSO PD
HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition
Finn et al 2009 Breast Cancer Research
Witkiewicz et al 2012 Cell Cycle
CDK46 inhibition remains effective in models resistant to endocrine therapy
Proliferation
CDK4 or CDK6
CycD1
ESR1
Oncogenic
Signals
ESR1
mutation Resistant
Model Naive
Model
Xenografts of therapy-resistant disease Fulvestrant resistant cells
ER
antagonists
CDK46
inhibitors
Finn et al 2009 Breast Cancer Research
Miller et al 2011 Cancer Discovery
Thangavel et al 2011 Endocrine related cancer
Wardell et al 2015 Clin Can Res
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Luminal B
High OncotypeDx RFS
High PAM50 ROR
Luminal A
Low OncotypeDx RS
Low PAM50 ROR
CTL
PD
CTL PD ICI ICI+PD0
200000
400000
600000
RL
U1
00
x1
0^
5 c
ells
ATP Levels
CTL
PD
ICI
ICI+PD
Oncotype Proliferation
Module
PAM50 Proliferation
Genes (Luminal AB)
CTL
PD
CTL
LY
CDK46i
Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition
Knudsen et al 2016 Oncotarget
Wardell et al 2015 Clin Can Res
Ladd et al 2016 Oncotarget
Knudsen et al 2016 Oncotarget
Oncotarget54130wwwimpactjournalscomoncotarget
the loss of an ER allele the MCF7-Y537SKO cell line
has lower ER expression relative to the parental MCF7
cell line (Figure S6A) Additionally when implanted in
mice supplemented with estrogen pellets we observed
continuous tumor growth of MCF7-Y537SKO cells in
vivo after removing the estrogen pellets (Figure S6B)
which is similar to previous overexpression studies [7]
We then assessed the effica cy of palbociclib or everolimus
in combination with fulvestrant Unlike CTC-174 no
single agent treatments exhibited in tumor regressions
(TGI of 52 50 and 62 for fulvestrant everolimus
and palbociclib respectively) (Figure 7A-7B) The
combination of palbociclib and fulvestrant resulted in a
greater tumor growth inhibition (5 regression) than
either agent alone similar to previous reports in a PDX
model with an ER-Y537S mutation [39] The combination
of everolimus and fulvestrant resulted in a 76 TGI
suggesting the combination of fulvestrant and everolimus
is additive in this model (Figure 7B) Together these data
provide a second ER mutant model demonstrating that
the addition of fulvestrant to palbociclib and everolimus
treatments will provide benefit in ER mutant breast
cancers
dIsc ussIo n
ER+ breast cancers bearing activating ER mutations
represent a new segment of endocrine resistant disease
with an unmet therapeutic need To investigate potential
strategies to target these tumors we developed an ER+
breast cancer CTX model from circulating tumor cells
of a patient that harbors a D538G ER mutation CTC-
174 This mutation promotes estrogen independent ER
activity and have been reported in patients who have
acquired endocrine resistance [7 9 10 40] Indeed
our model recapitulates endocrine therapy resistant
disease as shown by estrogen independent growth and
resistance to tamoxifen Using this model as well as in
vitro approaches we demonstrated that fulvestrant targets
the mutant ER protein for degradation but only provides
modest growth inhibition in vivo suggesting additional
pathways may promote resistance to endocrine therapy
Clinically combinatorial strategies for AI refractory
ER+ breast cancer have yielded encouraging results
The BOLERO-2 and PALOMA-1 trials both achieved
increased progression free survival by combining an
aromatase inhibitor with everolimus or palbociclib
respectively [16 22] Given that activating ER mutations
are acquired most frequently in patients who have
previously received an aromatase inhibitor [40] the
combination of everolimus or palbociclib with a SERD
such as fulvestrant may provide superior effica cy in these
patients by lowering ER expression and could potentially
increase overall survival [18] Recently the PALOMA-3
trial evaluating palbociclib combined with fulvestrant
demonstrated longer progression free survival compared
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
bull Conclusions ndash Discussion (10ndash15 minutes)
Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
Question cards are provided
Remember to complete your
evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat MD PhD
Medical Oncology Department
Hospital Cliacutenic of Barcelona
University of Barcelona
170271
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Disclosures
Applicability Company
(1) Advisory role Yes Nanostring Technologies
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Luminal A and B
Normal-like HER2-enriched
Basal-like Claudin-low
The intrinsic molecular subtypes of breast cancer
Prat A amp Perou CM Mol Oncol 20115(1)5-23
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Subtype distribution within HR+HER2ndash disease
Prat A et al Breast 201524 Suppl 2S26-35
51
34
10 5
Luminal A Luminal B HER2-E Basal-like
N=954
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy
Prat A et al BMC Med 201513303
N=451 patients within HR+HER2ndash disease
pCR RD Total
Luminal A 12 5 227 95 239
Luminal B 21 15 122 85 143
HER2-E 4 16 21 84 25
Basal-like 16 36 28 64 44
Plt0001
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
(includes tumour size) (includes tumour size
and nodal status)
Dowsett JCO 2013
MammaPrint OncotypeDX PAM50 ROR EndoPredict
Identification of patients with a very low risk of distant recurrence
HR+HER2-negative early breast cancer (T1-20-3 N+)
Patients who can be spared adjuvant multi-agent chemotherapy (or any other
additional drug) due to their low risk (lt10) of distant recurrence at 10-years with
endocrine therapy-only
Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
What about the prognostic role of the intrinsic subtypes in metastatic
HR+HER2-negative breast cancer
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Letrozole+placebo
Letrozole+lapatinib
R bull Phase III clinical trial
bull First-line therapy
bull 1286 patients with HR+ disease
bull No benefit of lapatinib in HR+HER2-
negative disease
bull Survival benefit of lapatinib in
HR+HER2+ disease
Johnston S et al J Clin Oncology 200927(33)5538-46
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
9161286 (71)
FFPE
821 (64)
RNA
Pre-treated
Luminal
Disease
nCounter
80 PRIMARY
TUMOURS
HR+HER2-neg (N=644)
PAM50 subtypes
EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes
Prat A et al JAMA Oncol 20162(10)1287-94
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
PFS OS
Letrozole (n=644)
Pro
gre
ss
ion
-fre
e s
urv
iva
l p
rop
ort
ion
10
08
06
04
02
00
10 20 30 40
Months
Luminal A
Luminal B
Basal-like
HER2-enriched
Ove
rall
su
rviv
al
pro
po
rtio
n
10
08
06
04
02
00
10 20 30 40
Months
P-value lt0001 P-value lt0001
50
Luminal A
Luminal B
Basal-like
HER2-enriched
0
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer
Prat A et al JAMA Oncol 20162(10)1287-94
Univariate Multivariate
Clinical variables x2 (P) x2 (P)
PAM50 subtype 35572 lt00001 31589 lt00001
Treatment 0648 0421 1010 0315
Prior endocrine therapy 24933 lt00001 27842 lt00001
Site of metastasis 0490 0484 0539 0463
Performance status 8075 0004 9719 0002
Num of metastases 13327 lt0001 15377 lt00001
Age 1603 0206 0875 0350
Type of tissue 3950 0047 6934 0008
Likelihood (x2) for PFS for all individual clinical variables
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)
aOnly patients with central laboratory data were included
CI confidence interval HR hazard ratio LET letrozole NE not
estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
PAL+LET (n=179)
PCB+LET (n=75)
Median (95 CI)
PFS mo
NE
(242ndashNE)
192
(163ndash239)
HR (95 CI)
P value
054 (036ndash079)
00015
PAL+LET (n=189)
PCB+LET (n=110)
Median (95 CI)
PFS mo
192
(141ndash222)
110
(82ndash137)
HR (95 CI)
P value
060 (045ndash081)
00006
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
0
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time months
Ki-67 le15a Ki-67 gt15a
PF
S
19m 28m 19m 11m
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Do intrinsic subtypes change when they recur
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Studying the biological differences between primary and metastatic breast cancer
Project Summary
bull 123 patients
bull FFPE paired tumor blocks
bull Primary vs 1 metastatic site
(mostly at first recurrence)
bull 70 HR+HER2-negative
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Primary Tumour
Gene expression data
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Metastatic Site
Pri
ma
ry T
um
or
Studying the biological differences between paired primary and metastatic breast cancer
bull Subtype Concordance=63
bull 54 of primary Luminal A tumors become non-Luminal A
bull 13 of primary Luminal AB become HER2-E
Cejalvo JM et al Cancer Res 2017 [Epub Mar]
Basal-like HER2-E LumA LumB
Basal-like 12 (92) 1 (8) 0 0
HER2-E 2 (15) 10 (77) 1 (8) 0
LumA 1 (2) 6 (13) 21 (46) 18 (39)
LumB 0 4 (13) 5 (17) 21 (70)
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Do other biology-based classifications of
HR+HER2-negative disease exist
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1
TCGA Nature 2012
disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
The genomic and
transcriptomic
architecture of 2000
breast tumors reveals
novel subgroups
Basal-like
HER2E
LumA
(1q16q)
LumB
LumA
11q133 amplification
(CCND1)
Curtis C et al Nature 2012486(7403)346-52
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Discussion
Biological complexity of HR+ breast cancer
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Targeting HR+HER2-negative disease beyond
endocrine therapy and chemotherapy
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
CDK46 inhibitors in breast cancer
bull Resistance to endocrine therapy
presents a major clinical challenge
bull The growth of HR+ breast cancer is
dependent on Cyclin D1 a direct
transcriptional target of ER
bull Cyclin D1 activates CDK 46 resulting in
G1ndashS phase transition and entry into
the cell cycle
bull Cell line models of endocrine resistance
remain dependent on Cyclin D1 and
CDK46
CDK cyclin-dependent kinase ER estrogen receptor
HR+ hormone receptor-positive
Figure adapted from Asghar 2015
Asghar U et al Nat Rev Drug Discov 201514130ndash146
Thangavel C et al Endocr Relat Cancer 201118333ndash345
M
G1 G2
S
CDK1
Cyclin B
CDK12
Cyclin A
pRB
P P P
E2F
pRB
E2F
S phase transcription program
G1S transition
Mitogenic signalling ERα
CDK2
Cyclin E
CDK46
Cyclin D
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
PALOMA-2 Subgroup analysis of PFS by biomarker
Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)
bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the
addition of palbociclib to letrozole While the PFS of the control group varied with several of these
markers palbociclib consistently improved PFS
bull Ki-67 by IHC did not further stratify patients
ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo
n HR (95 CI)
All patients 666 058 (046ndash072)
ER+
ERndash
504
62
057 (044ndash074)
041 (022ndash075)
Rb+
Rbndash
512
51
053 (042ndash068)
068 (031ndash148)
Cyclin D1+
Cyclin D1ndash
549
15
056 (044ndash071)
10 (029ndash346)
p16+
p16ndash
466
84
052 (040ndash067)
073 (039ndash136)
Ki-67 le20
Ki-67 gt20
318
235
053 (038ndash074)
057 (041ndash079)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95 CI)
All patients 666 058 (046ndash072)
ER status
le25th
gt25th to lt75th
ge75th
142
282
142
050 (032ndash078)
053 (037ndash074)
065 (041ndash105)
Rb status
le25th
gt25th to lt75th
ge75th
154
249
160
057 (036ndash088)
046 (032ndash067)
063 (042ndash095)
Cyclin D1
status
le25th
gt25th to lt75th
ge75th
141
247
176
041 (026ndash065)
069 (048ndash100)
052 (034ndash078)
p16 status
le25th
gt25th to lt75th
ge75th
140
258
152
074 (046ndash120)
062 (044ndash089)
033 (021ndash052)
HR (95 CI)
Favors PAL+LET Favors PCB+LET
Qualitative analysis Quantitative analysis
00 05 10 15 0 1 2 3 4
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
NeoPalAna phase II study
Palbociclib is not approved for use in EBC
C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status
ER oestrogen receptor HER2 human epidermal growth factor receptor 2
NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Primary endpoint
Complete cell cycle arrest
(CCCA defined as
Ki67le27) on C1D15
biopsy following 2 weeks of
palbociclib + anastrozole
Secondary endpoints
bull Clinical radiographic and
pathologic responses
bull Safety
bull CCCA rate and changes
in Ki67 by intrinsic
subtype and PIK3CA
mutation status
bull Molecular effect of
palbociclib and NGS of an
83-gene panel to explore
resistance mechanisms
bull Clinical stage II or III
bull ER+ (Allred 6ndash8)
bull HER2ndash breast cancer
bull ECOG PS 0ndash2
Single-arm phase II study
Anastrozole
(1 mg)
Palbociclib
(125 mg)
28-day (C0)
BIO
PS
Y
C0D1
SU
RG
ER
Y
BIO
PS
Y
C1D1
BIO
PS
Y
C1D15 Surgical
specimen
Off study
Ki67gt10
4 x 28-day cycles (C1ndashC4)
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Anastrozole alone induced CCCA
n=11 (26)
Adding P converted non-CCCA to CCCA
n=26 (60)
Persistent non-CCCA on both A + P
n=6 (14)
0
10
20
30
40
50
60
70
80
90
C0D1 C1D1 C1D15
Ki67 Response in Individual Pts
C1D15 gt 10
Off study
C1D15 gt 27
27
N=43
10
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
Ki67 Response by
Intrinsic Subtype
Luminal B (n=11) Luminal A (n=18)
0
20
40
60
80
C0D1 C1D1 C1D15
0
20
40
60
80
C0D1 C1D1 C1D15
Geo
metr
ic M
ean
s K
i67
Geo
metr
ic M
ean
s K
i67
0
20
40
60
80
100
C0D1 C1D1 C1D15
Basal-like
HER2-E
Rb E323fs
Non-luminal (n=2)
Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype
NCT01723774
Ma CX Presented at SABCS 2015 San Antonio Texas USA
Courtesy of CX Ma
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
7
12
20
C0D1 C1D1 C1D15 Surgery
Ki67 recovery at surgery after 4 weeks of palbociclib wash out
NCT01723774
Ma CX et al Clin Cancer Res 2017 [Epub March 7]
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
N=4600
bull Histologically
confirmed HR+HER2ndash
early invasive breast
cancer
bull Stage IIa or III
bull Pre- or
postmenopausal
women
bull Men eligible
bull le12 months since initial
pathologic diagnosis
bull Prior chemotherapy
allowed
RA
ND
OM
IZA
TIO
N
Palbociclib (2 years)
+ Endocrine therapy
(5ndash10 years)
Endocrine therapy
(5ndash10 years)
11
PENELOPE-B phase III study
N=1100 bull Early HR+
breast cancer
lsquohigh riskrsquo (CPS-
EG ge3)
bull Premenopausal
postmenopausal
bull Completed
taxane-based
neoadjuvant
therapy surgery
radiotherapy
RA
ND
OM
IZA
TIO
N
Palbociclib
(1 year)
+ SOC
Placebo
(1 year)
+ SOC
11
PALLAS phase III study
CDK46 inhibition in the adjuvant setting For how long
NCT01864746 NCT02513394
httpsclinicaltrialsgovct2showNCT01864746
httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC
Postmenopausal
Untreated BC I-II-III
HR+HER2-
Biopsies
Anastrozole +
Abemaciclib
TREATMENT
S
U
R
G
E
R
Y
15 days
N=220
Abemaciclib
Anastrozole 111 Anastrozole +
Abemaciclib
14 weeks
neoMONARCH phase II study
NCT02441946
Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC
neoMONARCH phase II study Results
bull Study met boundary for statistical significance at the interim analysis (boundary plt003)
bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more
than anastrozole alone
Abemaciclib is not approved for use in EBC
EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016
Geometric
mean change
Complete cell cycle arrest
Ki67 index lt27 at 2 weeks
0
ndash20
ndash40
ndash60
ndash80
ndash100
100
80
60
40
20
0
n=22 n=23 n=19
ndash710 ndash955 ndash931
5 16 13 Responders
227 696 684
Me
an
ch
an
ge
in
K6
7
exp
ressio
n (
)
Com
ple
te c
ell
Cycle
resp
on
se
ra
te (
)
GMR=022 (013 039)
Plt0001
024 (013042)
Plt0001
OR=78 (20 308)
0003
72 (20 267)
0000
Anastrozole 1 mg
Abemaciclib 150 mg
+ anastrozole 1 mg
Abemaciclib 1 mg
Can CDK46 inhibition accomplish similar
results as multi-agent chemotherapy in
HR+HER2-negative early breast cancer
Postmenopausal
Untreated Stage II-IIIA
HR+HER2-
AND
PAM50 LumA Node+
or LumB Node+-
Letrozole 25 mg +
Palbociclib 125 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
18 weeks
N=132
FEC x 3 ndashgt
Docetaxel x3 11
Palbociclib is not approved for use in early BC NCT02400567
httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Patients with
early and locally
advanced HER2+
and ER+ (gt10)
BC chemo-naiumlve
HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Histone
Acetyltransferases
(HAT)
Histone
Deacetylases
(HDAC)
HDAC inhibitors (eg entinostat)
Luminal A Luminal B
Chromatin structure regulates transcriptional activity
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
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Closing remarks
Erik Knudsen
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