F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal
Chair, ABC Global Alliance and ABC GuidelinesESMO Board of Directors & Director of Membership
ESO Breast Cancer Program Coordinator
The newest and most promising treatments
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DISCLOSURES SLIDE
Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics, Teva.
Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tesaro, Tigris, Wilex, Wyeth.
Non-Financial disclosures: Chair ABC Global Alliance and ABC Consensus Conference and Guidelines. Member/Committee Member of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC
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The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social workers, nurses and palliative care
specialists), is crucial.(LoE/GoR: Expert opinion/A) (100%)
GENERAL RECOMMENDATIONS
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Annals of Surgery 2016
THE ROLE OF EXPERIENCE AND EXPERTISE
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< 50 bcp vs > 150 bcp75% vs 84% survival at 5 years
CRUCIAL IMPORTANCE OF EXPERIENCE
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BREAST CANCER MOLECULAR SUBTYPES
Courtesy of MJ Brito
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MOLECULAR CLASSIFICATION OF BREAST CANCER - SURROGATES
Subtype Histological characteristicsSURROGATES
Biology/treatment
Luminal A • ER+• low grade/low proliferation
• indolent behaviour• sensitive to hormonal therapy
Luminal B • ER+ (lower expression than in luminal A)• high grade/high proliferation
• more aggressive behaviour than luminal A•less sensitive to hormonal therapy thanluminal A
Basal-like •“ Triple negative” (ER-, PR -, HER 2-)
• high grade/high proliferation
• aggressive behaviour• sensitive to chemotherapy
Her-2enriched
• HER 2+ • aggressive• sensitive to anti-HER-2 therapy• sensitive to chemotherapyRea
ch to
Rec
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Nucleus
A tumor cell in the Seventies
?
Cytoplasm
Courtesy of T. Tursz
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-cat
SOSGRB2
-cat
E-cad
HGF
GDNFMET EGFR
PTEN
NF2
?
? ? ?
E2FDP
P105-RBP
p16
CYC D1
CDK4
S-Phase genes
Tcf-4
-cat
WT1
p53 P21 Gene? Other targets ?
MLH1PMS2
MSH2GTBP(MSH3)
BRDCA2
BRCA1Rad51
Nucleus
?
ATM?
PI-3K
MAPKsCytoplasm
DNA mismatch
?
Hh
?
PTCH
SMO
Repair ?
RET
ELG-C
RNA Pol II
ELG-BVHL
-cat
? Target genes ?
? Target genes ?
EGF
GTP
APC
MEN1
NF1
RAS
RAF
Mdm-2
ELG-A
? Target genes ?
A tumor cell in the 2000’s
Courtesy of T. Tursz
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THE 2 MAIN PROBLEMS IN ONCOLOGY TODAY
✓ PATIENT SELECTION
✓ TUMOR RESISTANCE
GENERAL RECOMMENDATIONSTREATMENT
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Treatment Treatment
Response Resistance Response
Progression
THE MAJOR PROBLEM OF TUMOR RESISTANCE TO THERAPY
J. Ribeiro & F. Cardoso
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BIOPSY OF METASTATIC DISEASE
A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to confirm diagnosis particularly when metastasis is diagnosed for the first time. (LoE/GoR: I/B) (98%)
Biological markers (especially HR and HER-2) should be reassessed at least once in the metastatic setting, if clinically feasible.(LoE/GoR: I/B) (98%)
Depending on the metastatic site (e.g. bone tissue), technical considerations need to be discussed with the pathologist.
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SHOULD WE TREAT METASTATIC CANCER BASED ON THE BIOLOGY OF THE PRIMARY OR BIOPSY?
REASSESS BIOLOGY AT TIME OF RECURRENCE IS CRUCIAL
• Biology changes every time we give a new treatment
ONGOING EVALUATION OF DISEASE STATUS & BIOLOGY
But, SERIAL BIOPSIES are very difficultReach
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PET-CT
whole body CT
whole body MRI
LIQUID BIOPSIES
NANOTECHNOLOGY
PERFORM MINIMAL OR NON-INVASIVE SERIAL EVALUATIONS OF
DISEASE STATUS/BIOLOGY
IMAGING & FUNCTIONAL IMAGING
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The “bomb”
Tumor cell in division
The “missiles”
Chemotherapy Endocrine Therapy Ant-HER-2 therapy
Tumor cell with hormonal receptors
(about 2/3 of BC)
Tumor cell with HER-2 receptors
(about 1/5 of BC)
THE « WEAPONS » OF MEDICAL ONCOLOGY
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The newest and most promising treatments
for Metastatic/Advanced Breast Cancer
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TREATMENT TAILORING IN ABC
Treatment choice should take into account at least these factors: HR & HER-2 status, previous therapies and their toxicities, disease-free interval, tumor burden (defined as number and site of metastases), biological age, performance status, co-morbidities (including organ
dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological factors, available therapies in the patient’s country and patient preference.
(LoE/GoR: Expert opinion/A) (100%)Tailoring Therapy In Metastatic Breast Cancer
TAILOR FOR THE PATIENT TAILOR FOR THE DISEASEboth biologically and clinically
INDIVIDUALIZEDTREATMENT
Target
PATIENT PREFERENCES (Incurable setting; Quality & Quantity of Life)
PATIENT CHARACTERISTICS
DISEASE clinical CHARACTERISTICS
TUMOR CHARACTERISTICS (Biomarkers)
SEVERAL AVAILABLE OPTIONS FOR THE MANAGEMENT OF ER+/HER-2 neg ABC
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ENDOCRINE THERAPY
1st example of TARGETED THERAPY
ER: estrogen
receptor
THE TARGETTHE LIGAND
Aromatase inhibitors
TamoxifenFulvestrantRea
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Rec
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Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance.
(LoE/GoR: I/A) (93%)
ER POSITIVE / HER-2 NEGATIVE MBC
ALL guidelines are in agreement for this recommendationRea
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ESMO Guidelines for the Use of First-Line Endocrine Therapy in Postmenopausal HR+ ABC
Image adapted from Senkus & Cardoso F, et al. Ann Oncol. 2013, ESMO GUIDELINES
ENDOCRINE TREATMENT STRATEGY
ET2response
ET3 ET…response responseET1
CT
MAIN RESEARCH QUESTION:OPTIMAL SEQUENCERea
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Endocrine-Based Therapies for Breast
Cancer
Year Agent Mechanism
1977 SERMs
Tamoxifen
Toremifene
Antagonizes ER in breast tissue
1990s AIs
Anastrozole
Exemestane
Letrozole
Inhibit estrogen production in
postmenopausal women
2000s ERD
Fulvestrant
Impairs ER dimerization, increases ER
degradation, and disrupts nuclear localization
of ER
2010s Combinations
Exemestane/everolimus
Letrozole/palbociclib
Fulvestrant/palbociclib
Blockade of estrogen signaling and
prosurvival or cell cycle pathways
Slide credit: clinicaloptions.com
Lim E, et al. Oncology (Williston Park). 2012;26:688-694.
Croxtall JD, et al. Drugs. 2011;71:363-380.
Vidula N, et al. Clin Breast Cancer. 2016;16:8-17.
Mustonen MV, et al. World J Clin Oncol. 2014;5:393-405.
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The preferred 1st line ET depends on type and duration of adjuvant ET as well as time elapsed from the end of adjuvant ET; it can be an aromatase inhibitor, tamoxifen or fulvestrant.
(LoE/GoR: I/A) (84%)
ER POSITIVE / HER-2 NEGATIVE MBC
* for pre and peri- with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal womenRea
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Rec
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Estrogen
Cell
growth
Estrogen
receptor
Aromatase Inhibitors
ER & GROWTH FACTOR PATHWAYS & ENDOCRINE RESISTANCE
Cytoplasm
Nucleus
LBD
LBD
Cofactor complex
AF1 DBD
DBDAF1
SOS
(EG
FR
ShcRAS
RAF PI3K
Akt
m-TOR
MEK
HE
R2
P
P P
MAPK
Growth factor
receptor
GRB2
HDAC inhibitors (Entinostat)
Adapted from Denise Yardley et al, ASCO-Breast 2011
M-TOR inhibitor(Everolimus,
Sirolimus)
Tamoxifen
Anti-HER-2 agents
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Cell cycle CDKs
CDK 4/6 INHIBITORS (Palbociclib, Ribociclib, Abemaciclib)
They delay ET resistance by regulating the cell cycle (i.e. the cell clock)
Courtesy B. Sousa
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PFS: Investigator-Assessed - (ITT Population)
ITT=intent-to-treat; LET=letrozole; NR=not reached; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.
0 3 6 9 12 15 18 21 24 27 30 33
Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Pro
gre
ssio
n-F
ree
Su
rviv
al P
rob
abili
ty (
%)
444 395 360 328 295 263 238 154 69 29 10 2PAL+LET222 171 148 131 116 98 81 54 22 12 4 2PCB+LET
Number of patients at risk
Pro
gre
ss
ion
-Fre
e S
urv
iva
l, %
Time, months
PAL+LET
(N=444)
PCB+LET
(N=222)
Number of Events, n (%) 194 (44) 137 (62)
Median (95% CI) PFS 24.8 (22.1–NR) 14.5 (12.9–17.1)
HR (95% CI); 1-sided P value 0.58 (0.46–0.72); P<0.000001
PALOMA-2
Hortobagyi et al, ESMO 2016, updated ASCO 2017NEJM 2017
PFS (Investigator Assessment)
Ribociclib + Letn=334
Placebo + Letn=334
Number of events, n (%) 93 (28) 150 (45)
Median PFS, months (95% CI)
NR(19.3–NR)
14.7 (13.0–16.5)
Hazard ratio (95% CI) 0.556 (0.429–0.720)
One-sided p value 0.00000329
MONALEESA 2: PRIMARY ENDPOINT WAS MET EARLY
◆ PFS results by independent central review: hazard ratio 0.592 (95% CI: 0.412–0.852; p=0.002)
No. of patients at risk
Ribociclib + Let 334 294 277 257 240 226 164 119 68 20 6 1 0
Placebo + Let 334 279 264 237 217 192 143 88 44 23 5 0 0
Pro
bab
ility
of
Pro
gre
ssio
n-f
ree
Su
rviv
al (
%)
0
20
40
60
80
100
0 4 8 12 16 20 24 Time (months)
Let, letrozole; NR, not reached.
Monaleesa 2 - Updated results ASCO 2017
Median PFS
abemaciclib + NSAI: not reached
placebo + NSAI: 14.7 months
HR (95% CI): 0.543 (0.409, 0.723)
p = 0.000021
PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.508 (0.359, 0.723); p = 0.000102
MONARCH 3: Primary Endpoint: PFS (ITT)
Di Leo et al, ESMO 2017
1st Line CDK 4/6 INHIBITORS: EFFICACY
MONALEESA-7: RESULTS
CI, confidence interval; NR, not reached.1. Tripathy D et al. SABCS 2017;abst GS2-05 (oral); 2. Tripathy D et al. Lancet Oncol 2018;19:904–915.
MONALEESA-7:
• Ribociclib + ET reduced
the risk of progression by
45% vs the placebo arm
(p<0.0001)1,2
• Manageable safety profile
consistent with prior
studies of ribociclib1,2
Pro
bab
ilit
y o
f P
FS
(%
)
Time (months)
335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0
337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0
1086420
100
80
60
40
20
0
30282624222018161412
10
30
50
70
90
Placebo + ET
Ribociclib + ET
No. at risk
Placebo + ETRibociclib + ET
PFS (investigator assessed)1,2
Ribociclib + ETN=335
Placebo + ETN=337
Median PFS, months (95% CI) 23.8 (19.2–NR) 13.0 (11.0–16.4)
Hazard ratio (95% CI) 0.55 (0.44–0.69), p<0.0001
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Initial QoL Presentation: no difference in QoL!
HR QoL Monaleesa 2 (no significant differences)
Change From Baseline in Global Health Patient-reported
Outcomes, by Treatment Arm –EORTC QLQ-C30
Questionnaire
Time to definitive deterioration of the global health
status/QoL scale score of the EORTC QLQ-C30
questionnaire by at least 10%
Verma et al. ASCO 2017
Abemaciclib: no QoL yet reported
1st Line CDK 4/6 INHIBITORS: IMPACT ON QoL
TTD ≥10% IN GLOBAL HRQoL WAS DELAYED
WITH RIBOCICLIB VS PLACEBO
aPatients censored at progression; bSimilar results obtained with TTD ≥5%, ≥10%, and ≥15%.
No. at risk
Ribociclib + ET 335 282 256 236 218 201 188 145 112 69 43 41 15 3 0
Placebo + ET 337 260 218 198 178 158 132 97 67 38 18 17 6 1 0
Ribociclib + ET
N=335
Placebo + ET
N=337
No. of events 102 115
Months, median
(95% CI)
NR
(22.2–NR)
21.2
(15.4, 23.0)
Hazard ratio (95% CI) 0.70 (0.53–0.92), p=0.004
TTD ≥10% in global health status/QoL score of EORTC QLQ-C30a,b
Eve
nt-
free
pro
bab
ilit
y (%
)
100
80
60
40
20
0
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 2826
Placebo + ETRibociclib + ET
N. Harbeck et al, ESMO 2018Reach
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MONALEESA-7 Study Design
Stratification Factors• Liver/lung metastasis (yes/no)• Prior chemotherapy (yes/no)• Combination partner (NSAI/TAM)
Primary endpoint
•PFS (local)
Key secondary endpoint
•OS
Select secondary endpoints
•HRQOL
•ORR
•TTDD of ECOG PS
•Safety
Pre/perimenopausal
womena with
HR+/HER2− ABC
No prior ET for ABCb
≤ 1 prior CT for ABC
N = 672
Ribociclib
600 mg/day;
3 weeks on/1 week off
+
NSAI/TAMc + GOSd
n = 335
Placebo
3 weeks on/1 week off
+
NSAI/TAMc + GOSd
n = 337
ANA, anastrozole; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FSH, follicle-stimulating hormone; GOS, goserelin; HRQOL, health-related quality of life; NSAI, nonsteroidal aromatase inhibitor; ORR, objective response rate; TAM, tamoxifen; TTDD, time to definitive deterioration.a Premenopausal status was defined as either patient had last menstrual period ≤ 12 months or if receiving TAM or toremifene for ≤ 14 days, plasma estradiol and FSH must be in normal premenopausal range or in the case of induced amenorrhea, plasma estradiol and FSH must be in normal premenopausal range. Perimenopausal status was defined as neither premenopausal nor postmenopausal (prior bilateral oophorectomy, age ≥ 60 years, or FSH and plasma estradiol levels in normal postmenopausal range). Patients could not be ≥ 60 years of age. b
Patients who received ≤ 14 days of NSAI/TAM ± GOS were allowed. c TAM and NSAI were administered daily orally. TAM dose was 20 mg, LET dose was 2.5 mg. and ANA dose was 1 mg. d GOS 3.6 mg was administered by subcutaneous injection.
First Phase III trial with a CDK4/6 inhibitor exclusively in premenopausal patients
Dr Sara Hurvitz
Ran
do
miz
ed
1:1
S. Hurvitz, ASCO 2019
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Overall Survival
3
5
Dr Sara Hurvitz
Ribociclib + ET Placebo + ET
Events/N 83/335 109/337
Median OS, mo Not reached 40.9
HR (95% CI) 0.712 (0.535-0.948)
P value .00973
Kaplan-Meier
Estimate
Ribociclib +
ETPlacebo + ET
36 months 71.9% 64.9%
42 months 70.2% 46.0%
• ≈ 29% relative reduction in risk of death
Landmark Analysis
S. Hurvitz, ASCO 2019
RIBOCICLIB 1st line Pre-menopausal:
MCBS: 5
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2nd Line CDK 4/6 INHIBITORS: EFFICACY
0 2 4 6 8 10 12 14 16 18 20 22Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Pro
gre
ss
ion
-Fre
e S
urv
ival
Pro
bab
ilit
y (
%)
Palbociclib+Fulvestrant (N=347) Median PFS=11.2 months 95% CI (9.5, 12.9)Placebo+Fulvestrant (N=174) Median PFS=4.6 months 95% CI (3.5, 5.6)
HR=0.49795% CI (0.398, 0.620)1-sided p<0.000001
347 276 245 215 189 168 137 69 38 12 2 1PAL+FUL174 112 83 62 51 43 29 15 11 4 1PBO+FUL
Number of patients at risk
FINAL PROGRESSION-FREE SURVIVAL IN PALOMA-3 (ITT)1
38
FUL=fulvestrant; HR=hazard ratio; ITT=intent-to-treat; PAL=palbociclib; PBO=placebo.
1. Ibrance Summary of Product Characteristics; Pfizer Ltd; Kent, UK; 2018. Data cutoff date: 23 October 2015.
Absolute improvement in median PFS was 6.6 months
Cristofanilli et al, ESMO 2018
MONARCH 2: Primary Endpoint: PFS (ITT)
Median PFS
abemaciclib + fulvestrant: 16.4 months
placebo + fulvestrant: 9.3 months
HR (95% CI): .553 (.449, .681)
P < .0000001
PFS benefit confirmed by blinded independent central review (HR: .460; 95% CI: .363, .584; P < .000001)
Courtesy G. Sledge et al
• Ribociclib + fulvestrant
reduced the risk of
progression by 41% vs
placebo + fulvestrant
(p<0.001)1,2
No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
484
242
403
195
365
168
347
156
324
144
305
134
282
116
259
106
235
95
155
53
78
27
52
14
13
4
0
0
Time (months)
Pro
bab
ilit
y o
f P
FS
(%
)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
MONALEESA-3: FINAL PFS
CI, confidence interval; HR, hazard ratio.aInvestigator assessed.
1. Slamon DJ et al. ASCO 2018;abst 1000 (oral); 2. Slamon DJ et al. J Clin Oncol 2018;36:2465–2472.
PFSa,1,2 Ribociclib + fulvestrantN=484
Placebo + fulvestrantN=242
Median PFS, months (95% CI)
20.5 (18.5–23.5)
12.8 (10.9–16.3)
HR (95% CI) 0.59 (0.48–0.73), p<0.001
P. Fasching, ESMO 2018
aNo prior endocrine therapy for ABC;bUp to one line of prior endocrine therapy for ABC or relapse on/within 12 months of (neo)adjuvant endocrine therapy; cInvestigator assessed.
1. Slamon DJ et al. ASCO 2018;abst 1000 (oral); 2. Slamon DJ et al. J Clin Oncol 2018;36:2465–2472.
PFS BENEFIT CONSISTENT ACROSS TREATMENT SETTINGS
First linea Second line +
early relapseb
238
129
205
109
189
99
180
91
173
88
166
85
159
78
149
75
141
68
97
40
49
18
31
10
7
4
0
0
236
109
188
83
167
67
159
63
143
54
132
47
117
36
104
29
91
25
55
12
28
8
20
4
5
0
0
0
Pro
bab
ilit
y o
f P
FS
(%
)
26181614121086420 20 22 24
0
20
40
60
80
100
Time (months)
Pro
bab
ilit
y o
f P
FS
(%
)
26222016121086420 1814 24
0
20
40
60
80
100
Time (months)No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
PFSc,1,2
Ribociclib +fulvestrant
n=238
Placebo + fulvestrant
n=129Median PFS, months
NR 18.3
HR (95% CI) 0.58 (0.42–0.80)
PFSc,1,2
Ribociclib +fulvestrant
n=236
Placebo + fulvestrant
n=109Median PFS, months
14.6 9.1
HR (95% CI) 0.57 (0.43–0.74)
P. Fasching, ESMO 2018Rea
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OVERALL SURVIVAL IN PALOMA-3 (ITT)
Absolute improvement in median OS was 6.9 months
BUT
NOT STATISTICALLY SIGNIFICANT
0 6 12 18 24 30 36 42 48 54
Time (Months)
0
10
20
30
40
50
60
70
80
90
100O
ve
rall
Su
rviv
al
Pro
ba
bilit
y (
%)
Palbociclib+Fulvestrant (N=347)
Median OS=34.9 months
95% CI (28.8–40.0)
Placebo+Fulvestrant (N=174)
Median OS=28.0 months
95% CI (23.6–34.6)
Stratified HR=0.81
95% CI (0.64–1.03)
1-sided P=0.043
Unstratified HR=0.79
95% CI (0.63–1.00)
1-sided P=0.025
347 321 286 247 209 165 148 126 17PAL+FUL
174 155 135 115 86 68 57 43 7PBO+FUL
Number of patients at risk
Cristofanilli et al, ESMO 2018
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Abemaciclib: no QoL yet reported
2nd Line CDK 4/6 INHIBITORS: IMPACT ON QoL
PALOMA 3: Impact on Global QOL, Functioning and Symptoms
Time to Deterioration¥ in Pain Scores (QLQ-C30)
Conclusions
Compared to placebo + fulvestrant, addition of palbociclib to fulvestrant in endocrine resistant HR+/HER2– MBC patients was associated with:
❖ Significantly higher on treatment overall Global QOL scores
❖ Significantly greater improvement from baseline in emotional functioning and pain scores
❖ Significant delay in deterioration of pain
ECCO 2015: Harbeck et al
*Deterioration
defined as a ≥10-
point increase from
baseline.
+Censored.
Median: Palbociclib + Fulvestrant (8 mo) vs Placebo + Fulvestrant (2.8 mo); HR=0.642: P< 0.001
TTD ≥10% in global health status/QoL score of EORTC QLQ-C30a
GLOBAL HRQoL
NR, not reached.aPatients censored at progression.
Ribociclib + fulvestrant
N=484
Placebo + fulvestrant
N=242
No. of events, n (%) 139 (28.7) 79 (32.6)
Months, median
(95% CI)
NR
(22.1–NR)
19.4
(16.6–NR)
HR (95% CI) 0.80 (0.60–1.05)
No. at risk
Ribociclib + fulvestrant 351 308 286 264 251 228 205 177 105 56 49 10 0
Placebo + fulvestrant 175 150 142 123 108 97 81 69 40 18 18 3 0
Eve
nt-
free
pro
bab
ilit
y (%
)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (months)
Placebo + fulvestrantRibociclib + fulvestrant
484
242
P. Fasching, ESMO 2018
Ribociclib + fulvestrant, n 361 316 300 283 251 240 218 216 185
Placebo + fulvestrant, n 169 149 133 133 116 105 96 84 82
LS mean SEM
GLOBAL HRQoL IMPROVED/MAINTAINED VS
BASELINE WHILE ON TREATMENT IN BOTH ARMS
C, cycle; D, day; LS, least squares; S, screening; SEM, standard error of the mean.aEOT assessment occurred within 15 days from last dose of study drug.
8
4
0
–4
–8
C3D1 C5D1 C7D1 C9D1 C11D1 C13D1 C15D1 C17D1 C19D1 EOT
Time point
Placebo + fulvestrantRibociclib + fulvestrant
Change from baseline in global health status/QoL score of EORTC QLQ-C30
S/ /
184
113
Ch
ang
e fr
om
bas
elin
e
HRQoL
declines
at EOTa
P. Fasching, ESMO 2018
QoL similar in both armsReach
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10 MONTHS BENEFIT IN PFS 1st lineOS BENEFIT 1st line in Pre-menopausal6 MONTHS BENEFIT IN PFS in 2nd line
COST: 5.000 €/cycle
CDK 4/6 INHIBITORS (Palbociclib, Ribociclib, Abemaciclib)
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Everolimus (mTOR inhibitor)
PI3K
AKT
PTEN
mTOR
RAS
RAF
MEK
MAPK
ER target gene transcription
P P
EGFRHER2
E
E
ER
E
ER
E
ER
E
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4.6 to 6.9 ms benefit PFS
BOLERO-2 (18-ms FU): PFS Central
2
EVE 10 mg + EXE
PBO + EXE
Number of patients still at risk
HR = 0.38 (95% CI: 0.31-0.48)
Log-rank P value: <.0001
Kaplan-Meier medians
EVE 10 mg + EXE: 11.0 months
PBO + EXE: 4.1 months
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
485
239
427
179
359
114
292
76
239
56
211
39
166
31
140
27
108
16
77
13
62
9
48
6
32
4
21
1
18
0
11
0
10
0
5
0
0
0
Censoring times
EVE 10 mg + EXE (n/N = 188/485)
PBO + EXE (n/N = 132/239)0
20
40
60
80
100
Pro
bab
ilit
y (
%)
of
Ev
en
t
Time (week)
Piccart M, et al. ASCO 2012. Abstract 559.
BOLERO-2 (39-mo): Final OS Analysis
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Pro
bab
ilit
y o
f O
vera
ll S
urv
ival
Time, months
EVE+EXE (n/N = 267/485)
PBO+EXE (n/N = 143/239)
232
109
248
113
266
120
279
130
292
145
311
153
330
162
347
170
373
182
399
194
414
201
429
211
448
220
471
232
485
239
EVE+EXE
PBO+EXE
No. at risk
HR = 0.89 (95% CI, 0.73-1.10)Log-rank P = .14
Kaplan-Meier mediansEVE+EXE: 30.98 monthsPBO+EXE: 26.55 months
Censoring times
11
5
23
8
39
18
58
28
91
41
118
56
154
77
196
98
216
102
0
0
1
1
• At 39 months median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013): 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm
Piccart M, et al, EBCC 2014,LBA
Everolimus + AI
4 months “absolute benefit” in OSBUT
NOT STATISTICAL SIGNIFICANT
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Management of MUCOSITIS/STOMATITIS
Steroid mouthwash should be used for prevention of stomatitis induced by mTOR inhibitors (suggested schedule: 0.5mg/5ml dexamethasone,
10 ml to swish x 2 minutes then spit out qid). (LoE/GoR: I/B)
Early intervention is recommended. For > Grade 2 stomatitis, delaying treatment until the toxicity resolves and considering lowering the dose of the targeted agent are also recommended. Mild toothpaste and gentle hygiene are recommended for the treatment of stomatitis. Consider adding steroid dental paste to treat developing ulcerations.(LoE/GoR: Expert opinion/B).
Probably today MCBS = 3
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6 MONTHS BENEFIT IN PFS in 2nd lineNO OS BENEFIT SEEN
COST: 3.500 €/cycle
Everolimus
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PI3K
PTEN
PDK
1
Subtype HR+ HER2- TNBC
PIK3CA mut 40% 7-9%
PTEN mut/loss 2-4% 30-40%
PIK3R1 mut 3% 1%
AKT1 mut 2-3% Rare
Modified from Ma et al, Nat Rev Cancer 2015; ASCO 2018
Courtesy R. Dent, ESMO 2018
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European Society for Medical Oncology, 19–23 October, 2018, Munich, Germany
This presentation is the intellectual property of Fabrice Andre.
Contact [email protected] for permission to reprint and/or distribute.
SOLAR-1 (NCT02437318, Alpelisib) Primary endpoint:
Locally assessed PFS in the PIK3CA-mutant cohort
Data cut-off:
Jun 12, 2018
Alpelisib +
fulvestrant
(N=169)
Placebo +
fulvestrant
(N=172)
Number of PFS
events, n (%)103 (60.9) 129 (75.0)
Progressio
n99 (58.6) 120 (69.8)
Death 4 (2.4) 9 (5.2)
Censored 66 (39.1) 43 (25.0)
Median PFS
(95% CI)
11.0
(7.5–14.5)
5.7
(3.7–7.4)
HR (95% CI) 0.65 (0.50–0.85)
p-value 0.00065
• The primary endpoint crossed the
pre-specified Haybittle-Peto boundary
(one-sided p≤0.0199)
F. André et al, ESMO 2018
European Society for Medical Oncology, 19–23 October, 2018, Munich, Germany
This presentation is the intellectual property of Fabrice Andre.
Contact [email protected] for permission to reprint and/or distribute.
SOLAR 1
Adverse events in the total population*
*Safety profiles were similar in the PIK3CA-mutant and PIK3CA-non-mutant cohorts
AEs ≥20% in either arm, %
Alpelisib + fulvestrant
N=284
Placebo + fulvestrant
N=287
All Grade 3 Grade 4 All Grade 3 Grade 4
Any adverse event 282 (99.3) 183 (64.4) 33 (11.6) 264 (92.0) 87 (30.3) 15 (5.2)
Hyperglycemia 181 (63.7) 93 (32.7) 11 (3.9) 28 (9.8) 1 (0.3) 1 (0.3)
Diarrhea 164 (57.7) 19 (6.7) 0 45 (15.7) 1 (0.3) 0
Nausea 127 (44.7) 7 (2.5) 0 64 (22.3) 1 (0.3) 0
Decreased appetite 101 (35.6) 2 (0.7) 0 30 (10.5) 1 (0.3) 0
Rash 101 (35.6) 28 (9.9) 0 17 (5.9) 1 (0.3) 0
Vomiting 77 (27.1) 2 (0.7) 0 28 (9.8) 1 (0.3) 0
Decreased weight 76 (26.8) 11 (3.9) 0 6 (2.1) 0 0
Stomatitis 70 (24.6) 7 (2.5) 0 18 (6.3) 0 0
Fatigue 69 (24.3) 10 (3.5) 0 49 (17.1) 3 (1.0) 0
Asthenia 58 (20.4) 5 (1.8) 0 37 (12.9) 0 0
• Eighteen patients (6.3%) discontinued alpelisib due to hyperglycemia and 9 patients (3.2%) discontinued alpelisib
due to rash; no patients discontinued placebo due to either hyperglycemia or rash
F. André et al, ESMO 2018
European Society for Medical Oncology, 19–23 October, 2018, Munich, Germany
This presentation is the intellectual property of Fabrice Andre.
Contact [email protected] for permission to reprint and/or distribute.
SOLAR 1
Treatment exposure and dose adjustments
*The data cut-off for both groups was June 12, 2018.†1 patient in the placebo arm of the PIK3CA-mutant cohort did not receive fulvestrant or placebo.
Treatment exposure
PIK3CA-mutant* PIK3CA-non-mutant*
Alpelisib + fulvestrant
(N=169)
Placebo + fulvestrant(N=171)†
Alpelisib + fulvestrant
(N=115)
Placebo + fulvestrant
(N=116)
Exposure to alpelisib/placebo
Median duration of exposure to
alpelisib/placebo, months (range) [n exposed]5.5 (0.0–29.0) [168] 4.6 (0.0–30.1) [170] 5.6 (0.3–30.8) [115] 6.2 (0.5–29.5) [116]
Median relative alpelisib/placebo dose intensity,
%82.7 100 84.5 100
Alpelisib/placebo dose adjustments, n (%)
Patients with dose interruptions 125 (74.0) 55 (32.2) 80 (69.6) 31 (26.7)
Dose interruptions due to AEs 116 (68.6) 27 (15.8) 73 (63.5) 13 (11.2)
Patients with dose reductions 108 (63.9) 15 (8.8) 60 (52.2) 6 (5.2)
Dose reductions due to AEs 105 (62.1) 8 (4.7) 59 (51.3) 5 (4.3)
F. André et al, ESMO 2018
PI3K inhibitorsALPELISIB
6 Months benefit PFS
Only ~ 7% pretreated with CDK 4/6i
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How do HDAC inhibitors work?We can re-write our epigenetic code via writers, erasers and readers
HDACi can reprogram the carcinogenic epigenetic changes
Courtesy R. Dent, ESMO 2018
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HDAC inhibitorsChidamide?Entinostat?
4 Months benefit PFS
Not pretreated with CDK 4/6i
ACE (Chidamide) Trial: PFS in ITT Population
T i m e ( M o n t h s )
Pro
ba
bil
ity
of
Pro
gre
ss
ion
-fre
e S
urv
iva
l (%
)
0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
C h i d a m i d e + E x e m e s t a n e ( N = 2 4 4 )
M e d i a n p r o g r e s s - f r e e s u r v i v a l , 7 . 4 m o ( 9 5 % C I , 5 . 5 – 9 . 2 )
P l a c e b o + E x e m e s t a n e ( N = 1 2 1 )
M e d i a n p r o g r e s s - f r e e s u r v i v a l , 3 . 8 m o ( 9 5 % C I , 3 . 7 – 5 . 5 )
H a r z a r d R a t i o , 0 . 7 5 ( 9 5 % C I , 0 . 5 8 – 0 . 9 8 ) , P < 0 . 0 5
N o . a t R i s k
P l a c e b o + E x e m e s t a n e 1 2 1 7 6 5 4 4 3 3 8 2 7 1 9 1 4 8 2 2 1 1 0 0 0
C h i d a m i d e + E x e m e s t a n e 2 4 4 1 7 6 1 3 8 1 1 0 8 2 6 3 4 9 3 7 2 4 1 3 8 5 1 1 1 0
Z. Jiang et al, ESMO 2018
Non-hematologic Adverse Events
AEs > 20% in either arm, n (%)
Chidamide + Exemestane
(N=244)
Placebo + Exemestane
(N=121)
All Grade 3 Grade 4 All Grade 3 Grade 4
Hypokalemia 62 (25.4) 14 (5.7) 1 (0.4) 3 (2.5) 1 (0.8) 0
Nausea 61 (25.0) 1 (0.4) 0 7 (5.8) 0 0
Hyperglycemia 60 (24.6) 5 (2.1) 0 17 (14.1) 0 0
Hypocalcemia 58 (23.8) 2 (0.8) 0 3 (2.5) 0 0
Hypertriglyceridemia 57 (23.3) 10 (4.1) 2 (0.8) 15 (12.4) 0 0
Diarrhea 53 (21.7) 4 (1.6) 0 9 (7.4) 0 0
Aspartate aminotransferase increased 50 (20.5) 0 0 24 (19.8) 4 (3.3) 0
Alanine aminotransferase increased 49 (20.1) 0 0 20 (16.5) 2 (1.7) 0
Hematologic Adverse Events
AEs > 10% in either arm, n (%)
Chidamide + Exemestane
(N=244)
Placebo + Exemestane
(N=121)
All Grade 3 Grade 4 All Grade 3 Grade 4
Neutropenia# 199 (81.6) 102 (41.8) 22 (9.0) 31 (25.6) 1 (0.8) 2 (1.7)
Leukopenia 194 (79.5) 45 (18.4) 1 (0.4) 31 (25.6) 1 (0.8) 2 (1.7)
Thrombocytopenia 183 (75.0) 61 (25.0) 6 (2.5) 16 (13.2) 1 (0.8) 2 (1.7)
Anemia 78 (32.0) 9 (3.7) 0 22 (18.2) 2 (1.7) 0
#No febrile neutropenia was reported
Z. Jiang et al, ESMO 2018
ACE Study (Chidamide, HDAC inhibitor)
Phase III E2112: Exemestane ± Entinostat
in Advanced Breast Cancer
▪ Entinostat: oral, histone deacetylase inhibitor
▪ Primary endpoints: OS, PFS
▪ Secondary endpoints: ORR (CR or PR), TTD, toxicity
▪ Other outcomes: adherence, QoL, protein lysine acetylation
Pre/peri/postmenopausal
women and men with
HR+/HER2-, inoperable,
locally advanced or
metastatic BC, with
progression on/after NSAI
therapy
(N ≈ 600)
Entinostat PO Days 1, 8, 15, 22 +
Exemestane PO QD Days 1-28
(n ≈ 300)
Placebo PO Days 1, 8, 15, 22 +
Exemestane PO QD Days 1-28
(n ≈ 300)
Slide credit: clinicaloptions.comClinicalTrials.gov. NCT02115282.
Until disease
progression or
unacceptable
toxicity
*Pre/perimenopausal female and all male pts receive goserelin acetate SC Day 1.
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Cell
membrane
Ligand
binding
Activated receptor
Tumor Growth and
Metastases
Proliferation MigrationSurvival
Signal
transmition
HER-2 receptor TRASTUZUMAB
STOP
2nd EXAMPLE OF TARGETED THERAPY:
HER-2 RECEPTOR & TRASTUZUMAB
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• Longer OS: 25.1 vs. 20.3 ms (p=0.046)
• Longer TTP: 7.4 vs. 4.6 ms (p0.001)
• Higher RR: 50 vs. 32% (p0.001)
• Longer duration: 9.1 vs. 6.1 ms (p0.001)
MCBS: 5Rea
ch to
Rec
over
y Int
erna
tiona
l Con
fere
nce
2019
HER2 receptor
Trastuzumab
Pertuzumab
Subdomain IV of HER2
Dimerisation domain of HER2
DUAL BLOCKADE: TRANSTUZUMAB + PERTUZUMAB
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PI3K/Akt pathway
MAPK pathway
(Ras/Raf/
MEK/ERK)
Ligands
ErbB2Other ErbB
Proliferation Cell cycle, Survival
PI3K/Akt pathway
MAPK pathway
(Ras/Raf/
MEK/ERK)
Lapatinib
Lapatinib: TKI, small molecule, acts in the
intracellular domain
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Receptor-T-DM1 complex is internalized into HER2-positive cancer cell
Potent antimicrotubule agent is released once inside the HER2-positivetumor cell
T-DM1 binds to the HER2 protein on cancer cells
HER2
Trastuzumab-DM1
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HER-2 POSITIVE ABC: 1st line
CT + trastuzumab and pertuzumabor
CT + trastuzumabor
ET + trastuzumab +/- pertuzumab or lapatinib
HER-2 POSITIVE ABC: 2nd line and beyond
T-DM1or
CT + trastuzumabor
ET + trastuzumabReach
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TRASTUZUMAB:COST: 2.200 €/cycle
ANTI-HER2 THERAPIES
PERTUZUMAB:COST: 6.500 €/cycle
OS SURVIVAL BENEFIT IN ALL LINES
TDM-1:COST: 4.000 €/cycle
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Hope S. Rugo, MD
Abstract #1000
1. Nordstrom JL, et al. Breast Cancer Res. 2011;13(6):R123. 2. Stavenhagen JB, et al. Cancer Res. 2007;67(18):8882-8890.
Margetuximab: Fc-engineered to Activate Immune Responses
Fab: •Same specificity and affinity•Similarly disrupts signaling
Fc engineering:•↑ Affinity for activating FcgRIIIA
(CD16A)•↓ Affinity for inhibitory FcgRIIB (CD32B)
Margetuximab1,2
Fab:•Binds HER2 with high specificity•Disrupts signaling that drives
cell proliferation and survival
Trastuzumab
Fc:•Wild-type immunoglobulin G1 (IgG1)
immune effector domains•Binds and activates immune cells
Margetuximab Binding to FcγR Variants:
Receptor Type Receptor
Allelic Variant
Relative Fc Binding
Affinity Fold-Change
Activating
CD16A158F Lower 6.6x ↑
158V Higher 4.7x ↑
CD32A131R Lower 6.1x ↓
131H Higher ↔
Inhibitory CD32B 232I/T Equivalent 8.4x ↓
H. Rugo, ASCO 2019
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Hope S. Rugo, MD
Abstract #1000
Arm 1
Margetuximab (15 mg/kg Q3W) + chemotherapy
in 3-week cycles
HER2+ advanced breast cancer
• ≥2 prior anti-HER2 therapies, including pertuzumab
• 1-3 prior treatment linesin metastatic setting
• Prior brain metastasis ok if treated and stable
Study CP-MGAH22-04 (SOPHIA) Design1,2
Stratification:• Chemotherapy choice• Prior therapies (≤2 vs >2)• Metastatic sites (≤2 vs
>2)
HR=hazard ratio; CBA=central blinded analysis.
1. Rugo HS, et al. J Clin Oncol. 2016;34(suppl 15):TPS630. 2. Clinicaltrials.gov. NCT02492711. www.clinicaltrials.gov/ct2/show/NCT02492711. Accessed April 8, 2019.
Investigator’s choice of
chemotherapy
(capecitabine, eribulin,
gemcitabine, or vinorelbine)
Sequential Primary Endpoints
• PFS (by CBA; n=257; HR=0.67; α=0.05; power=90%)• OS (n=385; HR=0.75; α=0.05; power=80%)
Secondary Endpoints • PFS (Investigator assessed)• Objective response rate (by CBA)
Tertiary/Exploratory Endpoints
• Clinical benefit rate (CBR), duration of response (DoR)• Safety profile, antidrug antibody• Effect of CD16A, CD32A, and CD32B on margetuximab
efficacy
Arm 2
Trastuzumab(8 mg/kg loading → 6 mg/kg Q3W)
+ chemotherapy
in 3-week cycles
1:1 Randomization
(N=536)
H. Rugo, ASCO 2019
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Hope S. Rugo, MD
Abstract #1000
SOPHIA TRIAL: PFS Analysis in ITT Population
24% Risk Reduction of Disease ProgressionCentral Blinded Analysis (Primary Endpoint)
• PFS analysis was triggered by last randomization on October 10, 2018, after 265 PFS events occurred
ITT population: N=536. CI=confidence interval.
Margetuximab + Chemotherapy
(n=266)
Trastuzumab + Chemotherapy
(n=270)
# of events 130 135
Median PFS (95% CI)
5.8 months (5.52–6.97)
4.9 months (4.17–5.59)
HR by stratified Cox model, 0.76(95% CI, 0.59–0.98)
Stratified log-rank P=0.033
H. Rugo, ASCO 2019Reach
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DS-8201a: a HER2-targeting Antibody-drug Conjugate
• DS-8201 is a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker
• Designed to deliver CT inside cancer cells and reduce systemic exposure in comparison to traditional CT
• Activity in HER2+ and “HER2 low”
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TM
K
Overall survival according to subtype
Fietz, T., Tesch, H., Rauh, J., Boller, E., Kruggel, L., Jänicke, M., Marschner, N., 2017. Palliative systemic
therapy and overall survival of 1,395 patients with advanced breast cancer – Results from the prospective
German TMK cohort study. The Breast 34, 122–130, 2017
Prospective German TMK cohort study
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Heterogeneity of TRIPLE NEGATIVE BC: TNBC Classification
Le Du F. Oncotarget. 2015;6:12890-12908. This work is licensed under a Creative Commons
Attribution 3.0 Unreported License.Slide credit: clinicaloptions.com
Basal-like (BL)
TNBC
Mesenchymal-like TNBC
(ML-TNBC)Immune-associated
(IM) TNBC
Luminal/apocrine (LA) TNBC
HER2-enriched (HER2e)
TNBC
Immune signature
BL2
Cell cycleDNA damage
BLcytokeratine
Growth signaling(EGF, IGF)
Low proliferation
ARPathway
IM
Claudin-Low
BL1
M
Normal BL
LA/LB
HER2e
LAR
PI3K mutations
EMT signature:cell motility
growth factor signaling (TFG6, Notch,
Wnt/β-catenin, Hedgehog)
Angiogenesis
MSL
Lehmann's classification
PAM50/claudin-low classificationReach
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TRIPLE NEGATIVE ABC
For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations.
Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC.
(LoE/GoR: I/A) (98%)
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Lord and Ashworth Science (2017) Based on work of Yves Pommier and others
PARP INHIBITORS– mechanism of action (SYNTHETIC LETHALITY)
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Specific tumor cell killing
HR
rep
air
Few normal tissue effectsNormal tissue cells
DNA repair
DNA repair
Base excision DNA repair
Homologous recombination(HR) repair
BRCA1/BRCA2 deficientTumor cells
HR
rep
air
PARP inhibitor
Base excision DNA repair
PARP inhibitor
Base excision DNA repair
HR
rep
air
Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
The principle of synthetic lethal tumour targeting
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R
Potent PARP inhibitor
at MTD as continuous
exposure
Physician Choice
within SOC options
Capecitabine
or
Vinorelbine
or
Eribulin
or
Gemcitabine
gBRCA1 / BRCA2 Carriers
Advanced anthracycline
taxane resistant breast
cancer
Primary
endpoint
PFS
Niraparib – BRAVO Trial EORTC / BIG
Talazoparib– EMBRACA - NCT01945775
Olaparib - OLYMPIAD NCT02000622
National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/results?term=NCT01945775 and https://clinicaltrials.gov/ct2/results?term=NCT02000622 . Accessed: September 27, 2015.
How does PARP inhibition compare with CT in ABC?
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PARP Inhibitors in BRCA+ ABC
3 MONTHS DIFFERENCE IN PFS BUT BETTER QoLIMPACT ON OS?
COST: 7.000 €/month
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PRECISION MEDICINE
• NOT RECOMMENDED for ROUTINE CLINICAL PRACTICE:
• Multigene panels
• Circulating tumour DNA (ctDNA) assessment
• Immunotherapy
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Checkpoint inhibitors: ABC and EBC are totally different immune settingsAtezolizumab approval was based in a 2.5 months PFS difference
9
Primary PFS analysis: ITT population
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).NE, not estimable. Data cutoff: 17 April 2018. Median PFS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.
0 3 6 9 12 15 18 21 24 27 30 33Months
No. at risk:Atezo + nab-P 451 360 226 164 77 34 20 11 6 1 NE NE
Plac + nab-P 451 327 183 130 57 29 13 5 1 NE NE NE
Atezo + nab-P
(N = 451)
Plac + nab-P
(N = 451)
PFS events, n 358 378
1-year PFS
(95% CI), %
24%
(20, 28)
18%
(14, 21)
7.2 mo(5.6, 7.5)
5.5 mo(5.3, 5.6)
100
80
60
40
20
0
Pro
gre
ss
ion
-fre
e s
urv
ival Stratified HR = 0.80
(95% CI: 0.69, 0.92)
P = 0.0025
10
Primary PFS analysis: PD-L1+ population
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).Data cutoff: 17 April 2018.
0 3 6 9 12 15 18 21 24 27 30 33Months
No. at risk:Atezo + nab-P 185 146 104 75 38 19 10 6 2 1 NE NE
Plac + nab-P 184 127 62 44 22 11 5 5 1 NE NE NE
7.5 mo(6.7, 9.2)
5.0 mo(3.8, 5.6)
100
80
60
40
20
0
Pro
gre
ssio
n-f
ree s
urv
ival Stratified HR = 0.62
(95% CI: 0.49, 0.78)
P < 0.0001
Atezo + nab-P
(n = 185)
Plac + nab-P
(n = 184)
PFS events, n 138 157
1-year PFS
(95% CI), %
29%
(22, 36)
16%
(11, 22)
11
Interim OS analysis: ITT populationa
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).
Data cutoff: 17 April 2018. Median OS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.a For the interim OS analysis, 59% of death events had occurred. b Significance boundary was not crossed.
0 3 6 9 12 15 18 21 24 27 30 33 36Months
No. at risk:Atezo + nab-P 451 426 389 337 271 146 82 48 26 15 6 NE NE
Plac + nab-P 451 419 375 328 246 145 89 52 27 12 3 1 NE
21.3 mo(17.3, 23.4)
17.6 mo(15.9, 20.0)
100
80
60
40
20
0
Overa
ll s
urv
ival
Stratified HR = 0.84
(95% CI: 0.69, 1.02)
P = 0.0840b
Atezo + nab-P
(N = 451)
Plac + nab-P
(N = 451)
OS events, n 181 208
2-year OS
(95% CI), %
42%
(34, 50)
40%
(33, 46)
6
◆ Primary PFS analysis
(PFS tested in ITT and
PD-L1+ populations)
◆ First interim OS
analysis (OS tested
in ITT population, then,
if significant,
in PD-L1+ population)
IMpassion130 statistical testing
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).a α recycled if PFS/ORR testing is significant. Hazard ratio (HR)/P value–stopping boundaries are dependent on the OS analysis timing.
Atezo + nab-P
vs Plac + nab-P α = 0.05
PFS (primary)α = 0.01
OSa
• Interim
• Primary (α ≥ 0.04)
OS in ITT
population
OS in PD-L1+
population
1. PFS in ITT
populationα = 0.005
3. ORR in ITT
populationα = 0.001
4. ORR in PD-L1+
populationα = 0.001
2. PFS in PD-L1+
populationα = 0.005Rea
ch to
Rec
over
y Int
erna
tiona
l Con
fere
nce
2019
The cell cycle is the target of chemotherapy
Courtesy B. Sousa
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CHEMOTHERAPY (general)
Both combination and sequential single agent CT are reasonable options. Based on the available data, we recommend sequential monotherapy as the preferred choice for MBC.
Combination CT should be reserved for patients with rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease control.
(LoE/GoR: I/A) (96%)
ALL guidelines are in agreement for this recommendationRea
ch to
Rec
over
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nce
2019
• GOAL: to treat for as long as possible with a good QoL
• Then:
– TOXICITY PROFILE is crucial
– DOSE REDUCTIONS are acceptable and often needed (and better than interruptions)
– ORAL vs IV (convenient, cost-effective, maintain work responsibilities…)
– PATIENT PREFERENCES (oral treatment approaches and time saving drug delivery strategies are usually preferred by the patients)Rea
ch to
Rec
over
y Int
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nce
2019
Clinical Efficacy of Cytotoxic Agents
0
10
20
30
40
50
60
70
Vinorelbine Docetaxel Paclitaxel Doxorubicin Epirubicin Capecitabine Gemcitabine 5-FU
Ove
rall
Re
spo
nse
Rat
e (
%)
From: Hamilton A. J Clin Oncol. 2005; 23:1760-1775; Swart R. Medscape Reference. March 28, 2011, http://emedicine.medscape.com/article/1946040-overview.
Research question:
BEST SEQUENCE!?
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LIPOSOMAL TECHNOLOGY“Old” agents with new technology
Doxorubicin Liposomal Doxorubicin Pegylated Liposomal Doxorubicin
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