emerging therapies for triple negative breast...
TRANSCRIPT
Emerging Therapies for
Triple Negative Breast Cancer
Joseph A. Sparano, MD Professor of Medicine & Women’s Health
Albert Einstein College of Medicine
Associate Chairman, Department of Oncology
Montefiore Medical Center
Bronx, New York
Overview
• Clinical Features
• Biology and Disease Classification
• Cytotoxic Therapy
• PARP Inhibitors
• Biological Agents
• Immune Checkpoint Blockade
• Clinical Trials & Novel Approaches
Triple-Negative Disease Compared with Other
Phenotypes in the California Cancer Registry Study Bauer et al. Cancer 2007: 109; 721
Parise et al. The Breast Journal 2009: 15: 593
• Population-based study
– 6370 with “triple-negative” disease compared with 44,704 “other” cases (12% of all cases)
• TNBC more likely to be associated with
– Younger age (<40): OR 1.53
– Non-Hispanic black race (OR 1.77) or Hispanic ethnicity (OR 1.23)
– Higher grade (72% grade 3)
– More advanced stage (66% >/= stage II vs. 50% ER+HER2-)
– Poorer 5 year RFI irrespective of stage
• TNBC: 76% (similar to 76% for HER2-Pos)
• HR-Pos, HER2-Neg: 94%
– Greater propensity for lung and brain mets
Annual Hazard Rate of Recurrence by Breast Cancer Subtype in E1199:
Node-Positive & High-Risk Node Negative Breast Cancer Treated with
AC-Taxane Chemotherapy Plus Endocrine Therapy
0
.00
0.0
30
.06
0.0
90
.12
0.1
5
Recu
rren
ce h
azard
ra
te
0 2 4 6 8 10 12
Years Since Randomization
ER+/PR+
HER2+
TN
Biology and
Disease Classification
Breast cancer intrinsic subtypes by gene expression profiling
Perou et al. Nature 2000; Parker et al. JCO, 2009
Luminal A Luminal B ERBB2+ Basal NormL
Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844
Luminal Epithelial Cells
Low molecular wt CK 7, 8, 18 and 19
Mucin, BCL2, Hormone Receptors
Basal Cells (Myoepithelial cells)
High molecular wt CK 5, 6, 14 and 17
SMA, Calponin, p63, P-caderin
Perou C, et al. Nature 460:747-752, 2000
Terminal Duct Lobular Unit (TDLU)
Intrinsic Subtype Frequencies by ER/PgR Cut-
offs within TNBC Across 3 Adjuvant Trials: GIECAM 9906, MA5, MA12
ER/PR <1% (n=283) ER/PR <10% (n=331)
Cheang et al. ASCO 2012, abstract 1008
Biologic Basis for Poorer Outcome for
Triple Negative and/or Basal Disease
• Genomic instability
• Impaired DNA damage repair
– ATM Kinase
– CK1, claspin, EF1
• macrophage activation
• motility
• survival after colonization (ID genes)
Tommiska et al. Oncogene 2007 Nov 5 Epub
Verlinden et al. Cancer Res 2007; 67: 6574
Gupta et al. PNAS 2007; 104: 19506
XBP1 promotes TNBC by controlling the HIF1alpha pathway
• Unfolded protein response (UPR)
– adaptive response to hypoxia
– Mediated by endoplasmic reticulum (ER)-
localized membrane sensor (IRE1) and its
substrate (XBP1)
• XBP1 gene expression signature highly correlated
with HIF1-alpha and hypoxia signatures, and
associated with a poor prognosis
• XBP1 drives tumorigenicity by complexing with
HIF1-alpha and regulating expression of HIF1-
alpha targets via recruitment of RNA polymerase II
• Knockdown of of XBP1 enhances effectiveness of
cytotoxic therapy in an MDA 231 xenograft model
Chen et al. Nature 2014
BRCA Mutations & TNBC
• Up to 20% of unselected patients
• Up to 50% of patients with a strong
family history
• 50% of mutation carriers don’t have a
strong family history
Gonzalez-Angulo et al. JCO 2011
Bayraktar et al. BCRT 2011
BRCA1-Deficient Cells are Hypersensitive to Cisplatin
Tassone P et al. Br J Cancer 2003; 88:1285-1291
BRCA-deficient cell line – HCC1937
BRCA Proficient - MCF-7 (ER-pos) & MDA-MB-231 (ER/PR-Neg)
TNBC Subtypes 21 publicaly available gene expression breast cancer datasets, 587 TNBCs
Basal-like 1 (BL1): Cell-cycle, proliferation and
DNA damage response genes
Basal-like 2 (BL2): Growth factor signaling (EGF,
MET, Wnt/β-catenin, IGF1R)
Immunomodulatory (IM): Immune cell & cytokine
signaling (overlap with medullary signature)
Mesenchymal (M): Cell motility and differentiation
(Wnt, ALK, TGF-β)
Mesenchymal stem-like (MSL): Similar to M, but
increased growth factors signaling, low
proliferation, enrichment of stem cell genes
Luminal androgen receptor (LAR): Enriched in
hormonally-regulated pathways, androgen
receptor signaling. Displays luminal expression
patterns (molecular apocrine carcinomas)
Copyright © 2011, American Society for Clinical Investigation
Lehmann BD, et al. Journal of
Clinical Investigation, 2011
Are the Subtypes Clinically Relevant? Maybe
• Basal Cisplatin
• LAR Bicalutamide
• Mesenchymal-like
Src inhibition
Cytotoxic Therapy
Gem/Carbo (GC) (N= 258)
Gemcitabine 1000 mg/m2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8
21-day cycles
Gem/Carbo + Iniparib (GCI) (N= 261)
Gemcitabine - 1000 mg/m2 IV d 1, 8
Carboplatin - AUC2 IV d 1, 8
Iniparib - 5.6 mg/kg IV d 1,4,8,11
21-day cycles
R
Study Population:
• Stage IV TNBC
• ECOG PS 0–1
• Stable CNS metastases allowed
• 0-2 prior chemotherapies for mTNBC
• Randomization stratified by prior chemo in
the metastatic setting:
• 1st-line (no prior therapy)
• 2nd/3rd-line (1-2 prior therapies)
Study Design: Multi-center, randomized open-label Phase III Trial
Schema
Crossover allowed
to GCI following
Disease Progression* (central review)
N = 519
*Prospective central radiology review of progression required prior to crossover
96% (n=152) of progressing patients crossed over to GCI at time of primary analysis
NCT00938652
0 2 4 6 8 10 12 14 16
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Months Since Study Entry
Pro
bab
ilit
y o
f P
rogre
ssio
n F
ree
Surv
ival
No. at risk
GC 258 171 116 63 38 18 6 1 0
GCI 261 187 138 83 53 11 2 0 0
No. at risk
GC 258 239 214 181 151 99 38 11 0
GCI 261 248 230 204 169 111 52 15 0
Efficacy Endpoints – ITT population
0 2 4 6 8 10 12 14 16
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
bab
ilit
y o
f S
urv
ival
Months
Pre-specified alpha = 0.04
PFS GC
(N=258)
GCI
(N=261)
Median PFS, mos
(95% CI)
4.1 (3.1, 4.6)
5.1 (4.2, 5.8)
HR (95% CI) 0.79 (0.65, 0.98)
p-value 0.027
Pre-specified alpha = 0.01
OS GC
(N=258)
GCI
(N=261)
Median OS, mos
(95% CI)
11.1 (9.2, 12.1)
11.8 (10.6, 12.9)
HR (95% CI) 0.88 (0.69, 1.12)
p-value 0.28
Relation Between BRCA Mutation Status and
Response to Neoadjuvant Platinum Trial Characteristics Regimen No. pCR
Byrski BRCA1+mut carriers Not-platinum-based 90 14 (16%)
BRCA1+mut carriers CDDP 75mg/m2 x4 12 10 (83%)
Silver Sporadic TNBC
(not BRCA1+mut
carriers)
CDDP 75mg/m2 x4 26 4 (15%)
BRCA1mut carriers CDDP 75mg/m2 x4 2 2 (100%)
Ryan Sporadic TNBCs
(not BRCA1+mut
carriers)
CDDP 75mg/m2 x4 +
bevacizumab 15 mg/kg
q3wk x3
51 8 (16%)
Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010
PrECOG 0105 Schema PI: Melinda Telli, MD
Every 21 days x 6 cycles
n = 80
Definitive
Surgery
Assess
Pathologic
Response
Carboplatin AUC 2 D 1, 8
Gemcitabine 1000 mg/m2 D 1, 8
Iniparib 5.6 mg/kg D 1, 4, 8, 11
Newly
Diagnosed
Stage I-IIIA (T 1cm by MRI)
Triple-negative (ER/PR ≤ 5%)
or
BRCA1/2
mutation
Primary Endpoint: Pathologic complete response (pCR) [no invasive disease in breast + axilla]
Secondary Endpoint: Correlation of gene expression profiles & gene copy number with response
Results ITT population
Pathologic Response (n=80)
All patients
*******
n = 80
BRCA 1/2
wild-type
n = 61
BRCA 1/2
mutant
n = 19
TN & BRCA
1/2 mutant
n = 16
pCR [RCB 0]; n (%) 29 (36%) 20 (33%) 9* (47%) 9* (56%)
90% CI 27–46 23–44 27-68 33-77
RCB 0/1; n (%) 45 (56%) 31 (51%) 14 (74%) 12 (75%)
90% CI 46-66 40-62 52-89 52-91
* One BRCA1 carrier had bilateral TNBC & achieved pCR in both breasts
Target: lower bound of 90% exact binomial CI pCR rate exceeds 25%
87.5% power to detect 15% absolute improvement from 25% to 40% in pCR rate (binomial test with 1-sided alpha level of 5%)
Homologous Recombination Deficiency
(HRD) Assay
Goal:
To detect a genomic HR deficiency ‘footprint’ in a tumor caused by various defects in the HR pathway
Potential to identify non-BRCA1/2 mutation carriers with ‘BRCA-like’ cancers who may benefit from DNA repair targeted treatment strategies
Assay development:
Association of genomic patterns of loss of heterozygosity (LOH) & HR deficiency assessed in ovarian cancer
Major Finding:
LOH regions of intermediate size were observed more frequently in tumors with defective BRCA1 or BRCA2
HRD Score = Count of the # of LOH regions of intermediate size (> 15 Mb and < whole chromosome) observed in the tumor genome
Abkevich V, et al. British Journal of Cancer, 2012
Rate of Favorable Response (RCB 0/1)
by HRD Score
p = 0.0001
Telli ML, Timms K, Hartmann A-R, Ford JM, et al. SABCS 2012; abstract PD09-04
HRD score
Non-responders
BRCA1/2 intact responders
BRCA1/2 mutant responders
Antitubulins Bind to Different Sites on Tubulin
Taxus brevifolia
Paciific yew tree
Paclitaxel
Taxus baccata
European yew tree
Docetaxel
Myxobacteria
Sorangium
cellulosum
Ixabepilone Eribulin
Marine sponge
Halichondria
okidai
Vinorelbine
Catharanthus
roseus
Rosy periwinkle
•Paclitaxel, docetaxel, and epothilone B bind
to subunits at inside surface
Vincas binds to
(+) ends and
along sides Eribulin binds
to (+) ends
31
0.0
0.2
0.4
0.6
0.8
1.0
PFS by Treatment
ER Positive, PgR Positive
Months
PF
S P
rob
ab
ilit
y
0 6 12 18 24 30
PB
P
P < 0.0001
Medians: 7, 14.1
0.0
0.2
0.4
0.6
0.8
1.0
PFS by Treatment
ER Negative, PgR Negative
Months
PF
S P
rob
ab
ilit
y
0 6 12 18 24 30
PB
P
P < 0.0001
Medians: 4.7, 8.6
E2100: Weekly paclitaxel alone or plus bevacizumab as first-line
therapy for metastatic breast cancer – outcomes by ER/PR expression
P P+B
All 17% 34%
Measurable
(79%)
17% 41%
P P+B
All 23% 37%
Measurable
(46%)
30% 51%
ER/PR Negative
ER and/or PR Positive
Phase III Trials of Capecitabine With or Without
Ixabepilone in Anthracycline and Taxane Pretreated or
Resistant Advanced Breast Cancer
Thomas ES, et al. J Clin Oncol. 2007;25:5210-5217; Sparano J, et al. J Clin Oncol. 2010;28:3256-6263.
Ixabepilone
40 mg/m2 day 1 q3w
Capecitabine
2000 mg/m2 days 1-14 q3w
Capecitabine
2500 mg/m2 days 1-14 q3w
Eligibility criteria:
• Locally advanced or
metastatic breast
cancer
• CA163-046 Trial:
– Anthracycline-
pretreated or
resistant
– Taxane-resistant
• CA163-048 Trial:
– Anthracycline-
pretreated
– Taxane-pretreated
R
A
N
D
O
M
I
Z
E
Resistance criteria for CA163-046:
Progression / recurrence:
(Neo)adjuvant: < 6 months anthracycline,
< 12 months taxane
Metastatic: < 3 months anthracycline,
< 4 months taxane
Capecitabine ± Ixabepilone in
Triple Negative MBC
Rugo H, et al. SABCS 2008. Abstract 3057.
Pooled triple negative subgroup (n = 443)
Efficacy Ixa + Cape
(n = 191)
Cape
(n = 208)
ORR 31% 15%
CR 3% 1%
PR 28% 14%
Median PFS 4.2 mo 1.7 mo
HR 0.63
P value < 0.0001
Median OS 10.3 mos
(n = 213)
9.0 mos
(n = 230)
HR 0.87
P value 0.18
Selected
Grade 3/4
AEs
Ixa + Cape
(n = 209)
Cape
(n = 226)
Neutropenia 70% 8%
Febrile
neutropenia
4% < 1%
Leukopenia 63% 5%
Peripheral
neuropathy
23% < 1%
Hand-foot
syndrome
14% 16%
Fatigue 11% 3%
Eribulin Study 301
• Global, randomized, open-label phase III trial (Study 301)
• Stratification:
Capecitabine 1250 mg/m2 BID orally
Days 1-14, q21 days
Eribulin mesylate 1.4 mg/m2 2- to 5-min IV
Day 1 & 8 q21 days
Randomization 1:1
Co-primary endpoint
• OS and PFS
• Secondary
endpoints
• Quality of life
• ORR
• Duration of response
• 1-, 2- and 3-year survival
• Tumor-related symptom
assessments
• Safety parameters
• Population PK
Patients (N = 1102)
Locally advanced or
MBC • ≤ 3 prior
chemotherapy
regimens (≤ 2 for
advanced disease)
• Prior anthracycline
and taxane in
(neo)adjuvant setting
or for locally
advanced or MBC
Kaufman PA, et al. SABCS December 7, 2012. Abstract S6-6.
Overall 0.879 (0.770, 1.003) 15.9 14.5
HER2 status
Positive 0.965 (0.688, 1.355) 14.3 17.1
Negative 0.838 (0.715, 0.983) 15.9 13.5
ER status
Positive 0.897 (0.737, 1.093) 18.2 16.8
Negative 0.779 (0.635, 0.955) 14.4 10.5
Triple negative
Yes 0.702 (0.545, 0.906) 14.4 9.4
No 0.927 (0.795, 1.081) 17.5 16.6
Subgroup HR (95% CI) Eribulin Capecitabine
Median (months)
ITT population
Overall Survival By Receptor Status
0.2 0.5 1.0 2 5
N = 755
N = 449
N = 284
Favors eribulin Favors capecitabine
Kaufman et al, SABCS– December 7, 2012 Kaufman PA. et al, SABCS December 7, 2012. Abstract S6-6.
PARP Inhibitors
DNA Damage Repair Pathways
Base
excision
repair
Single-
strand
breaks
(SSBs)
PARP
Double-
strand
breaks
(DSBs)
Recombination
repair
ATM
BRCA DNA-PK
HR NHEJ
Type of
damage:
Repair
pathway:
Repair
enzymes:
Bulky
adducts
Insertions
& deletions
O6-
alkylguanine
Nucleotide-
excision
repair
Mismatch
repair
Direct
reversal
XP,
polymerases MSH2,
MLH1 AGT
Poly (ADP-ribose) Polymerase (PARP)
DNA binding
domain Catalytic Domain
PARP homology domain
PARP-1
Automodification
domain
• Nuclear protein – 3 functional domains
– Amino terminal: DNA binding
– Automodification: autoribosylation (protein-protein interactions)
– C-terminal: catalytic domain – transfer ADP-ribose from NAD+ to protein
acceptors, forming pADPr (2x higher charge density than DNA)
• DNA damage
– PARPs recruited to altered DNA, catalytic activity ↑ up to 500-fold
– pADPr localization to DNA and recruitment of proteins (eg, XRCC1)
which assemble and activate DNA base excision repair
– NAD+ and ATP depletion contribute to cell death
44
History of Poly(ADP-ribose) Polymerase (PARP) as a Therapeutic Target Chambon et al. Nature Cancer Reviews 2010
• Discovery of PARP
– 1963: Nuclear enzymatic activity that synthesizes an adenine containing
RNA-like polymer (Chambon et al)
– 1966-67: Confirmed by others, identified as PARP (Nishizuka et al)
• Discovery of PARP Function
– 1979: PARP activated by DNA strand breaks (Juarez-Salinas et al)
– 1980: PARP participates in DNA repair (Durkacz et al)
– 1986: PARP1 hyperactivation leads to NAD+ and ATP depletion after
DNA damage & metabolic cell death (parthanotos) (Berger et al)
– 2000: PARP knockouts confirm role in DNA repair (Shall et al)
• Discovery of PARP Inhibitors
– 1980: PARP inhibitors enhance alkylators (Durkacz et al)
– 2005: PARP inhibitors toxic to BRCA deficient cells (Bryant et al, Farmer
et al)
46
Chambon et al. Biochem Biophsyic Res Comm, 1963; Nishizuka et al l. JBC, 1968; Juarez-Salinas, Nature,
1979, Durkacz et al. Nature, 1980; Berger et al, BBRC, 1986; Shall et al. Mut Res, 2000; Bryant et al, Naure
2005, Farmer et al. Nature, 2005;
PARP Inhibitors
BSI-201 (Iniparib) AG014699
ABT-888 (Veliparib)
CEP-6800
NN
N
ONH2
NH
F NH
NH
O
NH
O
R1
R2
NH
NH
NH2
O
O
Olaparib
All share 3-aminobenzamide ring
Benzamide Inhibitors
3-aminobenzamide
Cell
survival
Base Excision Repair
Synthetic Lethality: Selective effect of PARP-1 inhibition on cancer
cells with BRCA1 or BRCA2 mutation
Homologous Recombination
DNA Damage
PARP
Inhibitor
BRCA
Mutation
Cancer
cell death
PARP Inhibitors In Development
Compound Other names Phase
Olaparib (AZ) KU0059436, AZD2281 III
Veliparib (AbbVie) ABT888 III
Rucaparib (Clovis) PF01367338 , AG014699 I/II
Niraparib (Tesaro) MK4827 III
BMN-673 (BioMarin) II & III
CEP-9722 (Cephalon) I
E7016 (Eisai) I
PARP Inhibitors - single agent development in
BRCA mutation associated breast cancer
Best response (ITT) Olaparib 400 bid
(n=27)
Olaparib 100 bid
(n=27)
CR 1 (4%) 0
PR 10 (37%) 6 (22%)
SD 12 (44%) 12 (44%)
PD 4 (15%) 9 (33%)
Median PFS 5.7 mo 3.8 mo
Tutt, Lancet 2010 MRD 141-144 days
Olaparib Not Effective in Sporadic TNBC
Olaparib 400 mg po BID
Gelmon et al, Lancet Oncol 2011
Phase III OLympiAD (OLaparib in Advanced Disease)
Metastatic breast
cancer & BRCA
mutation carrier
Prior anthra/taxane
0-2 prior for MBC
No prior platinum
Physician’s choice
(capecitabine, vinorelbine, eribulin)
Olaparib
Primary endpoint: PFS (no cross-over)
Secondary: OS, PFS2
Planned sample size: 310 patients
Nearly identical studies planned with niraparib (BIG/EORTC) and BMN-673 (Industry-sponsored)
Adjuvant Olaparib in Localized Breast
Cancer and BRCA Mutation Carriers
Randomise 1:1
Double blind
N=1320
Olaparib 300 mg
BID x
12 months
Placebo
X 12 months
IDF
S
•Adjuvant ER-positive group will be added after pilot safety data with endcorine therapy
•Primary endpoint: IDFS
•HR 0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required
• assumes consistent treatment effect (HR=0.7) across patient groups
• N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx
5.5 to 6 years from FSI
•Study being managed by BIG & NRG/Alliance
Post neoadjuvant BRCA TNBC,
Non-PathCR
Assumptions:
- Control arm 3 year EFS ~ 60%
Post adjuvant TNBC
Node positive disease
Node neg & T ,> 2cm
Assumptions:
-Control arm 3 year EFS ~ 75%
Dis
tan
t DF
S; O
S
Phase I-II Trials of Veliparib in BRCA-Mutation
Associated Metastatic Breast Cancer
Somlo et al. ASCO 2014; Abstract 1021
Recommended phase II dosing:
• Veliparib monotherapy: 400 mg PO BID continuously
• Veliparib + carboplatin : 150 mg PO BID days 1-14 + carbo AUC5 q3 wks
Paclitaxel + Trastuzumab* +
New Agent A
Paclitaxel + New Agent C
Patient is on Study
Paclitaxel+ Trastuzumab
Paclitaxel + Trastuzumab* +
New Agent B
Paclitaxel
Paclitaxel + New Agent E
AC
AC HER 2 (+)
HER 2 (–)
Randomize
Randomize
Surgery
Surgery
Learn and adapt from each patient as
we go along
Paclitaxel + New Agent F
Paclitaxel + Trastuzumab* +
New Agent C
Paclitaxel + New Agent D
Paclitaxel + New Agent GH
MRI
Residual
Disease
(Pathology)
Key
I-SPY 2 TRIAL Design:
Learn, Drop, Graduate, and Replace Agents Over Time
I-SPY 2: Veliparib/Carboplatin Graduates in TNBC
SIGNATURE
Estimated pCR Rate (95% probability interval)
Probability
Veliparib +
Carbo is
Superior to
Control
Predictive
Probability of
Success in
Phase 3 Veliparib/
Carbo
Concurrent
Control
All HER2- 33%
(22-43%)
22%
(10-35%) 92% 55%
HR+/HER2- 14%
(4-27%)
19% (6-35%)
28% 9%
HR-/HER2- 52% (35-69%)
26% (11-40%)
99% 90%
Rugo et. al. SABCS 2013
Veliparib Phase III Trials in Breast Cancer
• Phase III Randomized Placebo-Controlled Trial of
Carboplatin and Paclitaxel with or without the PARP
Inhibitor Veliparib (ABT-888) in Metastatic or Locally
Advanced Unresectable BRCA-Associated Breast Cancer
• Phase III Randomized, Placebo-Controlled, Double-Blind,
Study Evaluating Safety and Efficacy of the Addition of
Veliparib Plus Carboplatin Versus the Addition of
Carboplatin to Standard Neoadjuvant Chemotherapy
Versus Standard Neoadjuvant Chemotherapy in Subjects
With Early Stage Triple Negative Breast Cancer (TNBC)
Clinical Trials with PARP Inhibitor BMN673
Phase III: Open-Label, Randomized, Parallel, 2-Arm, Study of
BMN 673 versus Physician’s Choice in Germline BRCA Mutation
Subjects with Locally Advanced and/or Metastatic Breast Cancer,
Who Have Received No More than 2 Prior Chemotherapy
Regimens for Metastatic Disease
Phase II: A 2-Stage, 2-Cohort Study of BMN 673 Administered to
Germline BRCA Mutation Subjects with Locally Advanced and/or
Metastatic Breast Cancer
• Cohort 1: previously responded to a platinum-containing
regimen for metastatic disease with disease progression > 8
weeks following the last dose of platinum
• Cohort 2: Received > 2 prior chemotherapy regimens and
who have had no prior platinum therapy for metastatic
disease
Biological Agents
BALI-1 Trial Cisplatin Cisplatin +
Cetuximab
No. 58 115
Response Rate 10.3% 20% P=0.11
Median PFS 1.5 mo. 3.7 mo. HR 0.67, p=0.03
Median OS 9.4 mo. 12.4 mo. HR 0.82, p=0.31
Baselga et al. J Clin Oncol. 2013 Jul 10;31(20):2586-92.
Miles et al. Ann Oncol 2013, 7/25/13 ahead of print
Median PFS 9.2 vs. 6.7 mo.
HR 0.64 (95% CI 0.58,
0.71) ORR: 49% vs. 32%,
p<0.0001
Paclitaxel 90mg/m2 weekly
x 3 q4 weeks /
Placebo 10 mg/kg q2w
Paclitaxel 90 mg/m2 weekly x 3 q4 weeks /
Bevacizumab 10 mg/kg q2w
Confirmatory Study Schema: MERiDiAN
Co-Primary Endpoints: PFS (All Patients) , PFS (VEGF high subset)
Secondary Endpoints: OS; ORR; Symptoms/QoL; Safety
MBC, HER2-Negative Chemo-naïve
N=480
Stratification
• VEGF-A (low/high) • Adjuvant therapy (yes/no) • Hormonal status (ER +/-) R
A N
D O
M I Z
E D
Immune Checkpoint Blockade
Loi et al.. J Clin Oncol 2013; 31: 860
Adams et al. JCO 2014
Systematic Review & Metaanalysis of TILs and Response to Neoadjuvant Chemotherapy
San Antonio Breast Cancer Symposium 2013 Murali Janakiram, MD
• Methods:
– 1147 reports in Pubmed, ASCO abstracts (2009 -2012), & Embase between 1/91-5/13
– 7 studies including 1641 patients met inclusion criteria
• Results:
– TIL ratio classified as either high or positive was associated with a significantly higher likelihood of achieving a pCR/near pCR after NAC
– Effect was driven mainly by a difference in in ER negative tumors and Her2 positive tumors
Subtype N Noof
studies
pCR% OR 95%CI
TILlow TILhighAll 1641 7 12.5% 28.6% 3.68 1.93–7.01
ER-/PR- 403 4 23.6% 41.3% 4.04 2.16–7.57Her2+ 326 3 16.9% 23.4% 5.61 1.80-17.47ER/PR+ 558 2 5.6% 11.5% 2.17 0.95–4.98
Reference Trials N (Subtype)
pCR Rates and TILs
Issa-Nummer, PLOSone 2013
Prospective Validation
GeparQuinto 313
(HER2-)
14.3% (<60% TILs)
36.6% (≥60% TILs)
Denkert, SABCS 2013
Prospective validation
GeparSixto 314
(TNBC)
TNBC (+Carbo)
45.7% (<60% TILs)
73.8% (≥60% TILs)
TNBC (-Carbo)
33.9% (<60% TILs)
42.6% (≥60% TILs)
Presented by: Shaveta
Vinayak, M.D., M.S.
Relationship Between TILs and Response to Neaodjuvant Therapy
“Cancers associated with BRCA1 mutations … showed more lymphocytic infiltrate (P for trend <.0001)…”
Presented by: Sridhar Ganesan, MD, PhD
WHY DOES AN IMMUNE INFILTRATE PREDICT FOR
SENSITIVITY TO CHEMOTHERAPY ?
1. CHEMOTHERAPY REVERSES IMMUNE TOLERENCE AND
INDUCES EFFECTIVE IMMUNE RESPONSE.
2. IMMUNE INFILTRATE IS A MARKER OF AN UNDERLYING
DNA REPAIR DEFECT
3. CHEMOTHERAPY KILLS LYMPHOCYTES , DEPRIVING
TUMOR CELLS OF GROWTH FACTORS (“lymphocyte
addiction”)
Immune Checkpoint Blockage as a Therapeutic Strategy
Ribas et al. NEJM 2012
B7 Family Expression in Triple Negative Breast Cancer
Unpublished data. Courtesy of X. Zang, Albert Einstein College of Medicine.
Topalian et al. NEJM 2012
Clinical Trials and
Novel Approaches
Genomic Sequencing vs. Gene Expression
Whole Exome Sequencing – 1% Genome
Coding regions only
Whole Genome Sequencing –100% Genome (22,000 genes)
Exons (coding), Introns (non-coding), & Intergenic Regions
Targeted Sequencing – 0.003% Genome
200-400 exons – potentially actionable mutations
Gene Expression Profiling
7 (BCI), 21 (Oncotype), 50 (PAM50), 70 (Mammaprint), others
Poor risk proflles identify patients with ER-pos, HER2 neg
disease & 0-3 pos nodes who derive greatest chemo benefit
Non-coding RNA
DNA methylation
Histone modfications
Researc
h &
D
iscovery
Clin
ica
l P
ractice
Proteomics
Presented by: Joseph A. Sparano, MD
Distribution of Mutations in TCGA
by Breast Caner Subtype
Presented by: Joseph A. Sparano, MD
427 Enrolled 407 MBC Bx 299 Genomics
195 Druggable Lesions 55 Genomic-driven Rx
SAFIR 01 Molecular-Driven Study Flow
(13%)
Andre F, et al. Lancet Oncol 2014
Most Activating Mutations are Rare
AURORA Initiative
Zardavas et al. BJC 2014
NCI MATCH • Molecularly profile 3000 patients with PD after Rx
– Multianalyte validated targeted NGS assay in CLIA lab
– Identify 1000 patients with tumors that have mutations
and/or amplifications in pathways targetable by existing
agents
• Assignment to receive targeted agents/regimens
– Commercial or experimental agents
– Phase II design for each agent with OR/PFS endpoint
– Rule based algorithms
• Level 1: FDA approved different tumor
• Level 2: Data from clinical trials in similar molecular abnormality
• Level 3: Plausible preclinical evidence that drug works against a
given tumors with a given molecular abnormality
Presented by: Joseph A. Sparano, MD
Barriers to Clinical Application
• Technical and Logical Gaps
– Tissue access & purity (eg, stroma, inflammation)
– Limited access to novel agents /combinations
• Biological Barriers
• Tumor heterogeneity
» Intra-cellular (multiple mutations)
» Inter-cellular (multiple clones)
» Stromal and immune effects
• Driver vs. passenger mutations
» Few “addictive”
» Most are uncommon/rare
• Clonal evolution
» Intrinsic/acquired resistance
» Need for combinations
Tumor Heterogeneity
A
B
C
B
C Drug A
B
B
B B
C
C
C
Clonal Evolution
A A
A
Driver vs. Passenger
Conclusions – Treatment of TNBC • Predictive biomarkers
– Evaluate for BRCA mutation – NCCN guidelines vs. population screen?
– Clinical utility of genomic sequencing uncertain
• Cytotoxic therapy
– Taxanes & platinum combinations have modest activity in MBC
– Capecitabine less effective than eribulin in MBC
– Platinums improve pCR rates as neoadjuvant therapy – effect of breast
conservation and recurrence unknown
• PARP Inhibitors
– Multiple ongoing trials will define role in mutation-associated and
sporadic TNBC
• Biologics
– Bevacizumab improves response and PFS, not survival – predictive
biomarkers needed - use limited due to rescinded FDA approval
– Anti-EGFR directed agents have modest activity & skin/GI toxicity