Inibidor de CDK4/6 no Tratamento do Cancer de
Mama Metástatico RH+, HER-2 negativo
Dr Antonio C Buzaid
Diretor Médico Geral
Centro Oncológico Antonio Ermírio de Moraes, Beneficência Portuguesa de São Paulo
Membro do Comitê Gestor
Centro de Oncologia Dayan-Daycoval, Hospital Israelita Albert Einstein
Disclaimer
De acordo com a resolução do Conselho Federal de Medicina nº 1595/2000 e Resolução da Diretoria Colegiada da ANVISA nº 96/2008, eu declaro os seguintes potenciais conflitos de interesse:
Pesquisa Clínica – Como investigador: Roche, MSD, BMS, Novartis, Pfizer
Apresentações científicas – Como palestrante: Roche, MSD, BMS, Novartis, Pfizer, Eisai, AstraZeneca
Atividades de Consultoria – Como membro de Advisory Boards: Roche, MSD, BMS, Novartis, Pfizer, Eisai, AstraZeneca e Blau
Declaro não ter ações em bolsa de valores das empresas supracitadas.
Meus pré-requisitos para participar destas atividades são o intercâmbio científico, a autonomia do pensamento científico, independência de opinião e liberdade de expressão, aspectos estes respeitados pela Novartis.
Esta apresentação pode conter informações que não constam nas bulas aprovadas dos produtos Novartis . Estas informações têm o intuito de fornecer a você os dados científicos pertinentes para tirar suas próprias conclusões e para tomar suas próprias decisões. A Novartis não corrobora a promoção de seus produtos de uma forma que não esteja de acordo com suas bulas aprovadas.
Sr. George Beatson
Em 1896 publicou artigo entitulado “On
Treatment of Inoperable Cases of
Carcinoma of the Mamma: Suggestions for
a New Method of Treatment, with
Illustrative Cases”. Ele é considerado o pai
da terapia anti-hormonal em câncer de
mama desde que ele foi o primeiro a
descrever remissões na doença
metastática após SOB.
Linha Histórica da Terapia para Câncer de Mama Metastático RH+
Ooforectomia MSREs• Tamoxifeno
• Toremifene
IAs• Anastrozol
• Letrozol
• Exemestano
ERDs• Fulvestranto
ERDs
• Fulvestranto
em altas doses*
1896 1977 1990s 2002 2010
Alvo: mecanismos
de resistênciaendócrina
2012
EstrógenosAndrógenos2
1960
Transpondo a Resistência Hormonal
Racional do uso de Inibidores de CDK4/6 no Ca de Mama avançado RH+
1. Chumsri S, et al. J Steroid Biochem Mol Biol. 2011;125(1-2):13-22; 2. Musgrove EA, et al. Nat Rev Cancer.
2011;11(8):558-572; 3. Finn RS, et al. BCR. 2009;11(5):R77; 4. Dickson MA. CCR. 2014;20(13):3379-3383.
• Estrogen stimulates expression of cyclin
D1 thereby facilitating activation of
CDK4 & 6 and cell cycle progression 1,2
• Continuous inhibition leads to sustained
cell cycle arrest which may lead to
senescence or apoptosis, while short
term inhibition ledas to reversible arrest
with rebound effect 3,4
Mecanismo de ação
1. Altucci L et al. Oncogene 1996; 12(11): 2315-242. Meyerson M et al. Mol Cell Biol 1994; 14(3): 2077-863. Torres-Guzmán R et al. Oncotarget 2017; (Ahead of print)4. Gelbert et al. Invest New Drugs 2014; 32(5): 825-37
• PALOMA-1
• PALOMA-2
• MONALEESA-2
• MONARCH-3
iCDK4/6 na Primeira Linha na Pós-Menopausa
PALOMA 1: Estudo de Fase II, Randomizado de Palbociclibe +
Letrozol vs. Letrozol no Tratamento de Primeira Linha em Pacientes
Pós-Menopausa com Ca de Mama avançado (TRIO-18)
Finn R, et al Lancet Oncology 16:25, 2015
PALOMA-1/TRIO-18: Sobrevida Livre de Progressão
Finn R, et al Lancet Oncology 16:25, 2015
0
10
20
30
40
50
60
70
80
90
100
Number at riskPalbociclib plus letrozole
Letrozole
23 6320 241 2 160 284 48 0
Both cohorts
51
83
2814
216
4728
3619
8481
133
6748
6036
1
Palbociclib plus letrozoleLetrozole
HR 0・488 (95% CI 0・319–0・748; one-sided p=0・0004)
PALOMA-2 (Estudo de Fase III) TRIO-1008
Finn R, et al. N Engl J Med 375: 1925, 2016
Estudo Fase 3
N=666
- Mulheres na pós-menopausa
- Ca mama avançado ou com
recorrência regional RH+, HER
neg, sem terapia prévia para
doença avançada
- PD durante ou após Tam
adjuvante
- De novo ou >12 meses após IA
adjuvante Ra
nd
om
iza
çã
o 2
:1
Placebo + Letrozol
Palpociclibe (125mg por 21 dias com 7 dias de intervalo)
+ Letrozol
Endpoint Primário:
- Avaliação SLP pelo investigador por RECIST v1,1
Estratificação:
- Local da doença: visceral vs. Não-visceral
- Terapia prévia: Endócrina vs. Não-endócrina
- Intervalo livre de doença: de novo vs. <12m vs.
>12m
- Endponts secundários: SG, TRG, Segurança, FC/FD,
Biomarcadores, QV
- Avaliação da doença a cada 12 semanas
- Cintilografia óssea a cada 24 semanas
Abreviações: SG: sobrevida global; TRG: taxa de resposta global; FC/FD: farmacocinética/farmacodinâmica; QV: qualidade de vida
Suposição estatística: SLP mediana 9m vs. 13m
PALOMA-2: Objetivo Primário
100
90
80
70
60
50
40
30
20
10
0So
bre
vid
a L
ivre
de
Pro
gre
ssã
o, %
0 3 6 9 12 15 18 21 24 27 30 33
Número de pacientesPAL + LETPCB + LET
444
222
395
171
360
148
328
131
295
116
263
98
238
81
154
54
69
22
29
12
10
4
2
2
PAL + LET
(n = 444)
PCB + LET
(n = 222)
Número de Eventos, n (%) 194 (44) 137 (62)
SLP Mediana (IC 95%) 24,8 (22,1 – NR) 14,5 (12,9 – 17,1)
HR (IC 95%); 1-sided P value 0,58 (0,46-0,72; P < 0,000001
Tempo (meses)
Finn R, et al. N Engl J Med 375: 1925, 2016
Sobrevida Livre de Progressão
PALOMA-2: Revisão Central SLP
100
90
80
70
60
50
40
30
20
10
0So
bre
vid
a L
ivre
de
Pro
gre
ssã
o, %
0 3 6 9 12 15 18 21 24 27 30 33
Número de Pacientes:PAL + LETPCB + LET
444
222
384
167
344
144
319
131
281
111
252
94
228
76
149
49
68
22
31
12
9
3
2
2
PAL + LET
(n = 444)
PCB + LET
(n = 222)
Número de Eventos, n (%) 152 (34) 96 (43)
Mediana SLP (95% CI) 30,5 (27,4 – NR) 19,3 (16,4 – 30,6)
HR (95% CI); 1-sided P value 0,65 (0,51 – 0,84); P = 0,0005
Tempo (meses)
Finn R, et al. N Engl J Med 375: 1925, 2016
PALOMA-2: Objetivos Secundários
Finn R, et al. N Engl J Med 375: 1925, 2016
Palbociclib +
Letrozole
(N = 444)
Placebo +
Letrozole
(N = 222)
Odds ratio
(95% CI)
1-Sided
P Value
(Exact)
ITT population 444 222
Objective response rate, % (95% CI)42%
(37.5 - 46.9)
35%
(28.4 - 41.3)
1.40
(0.98 - 2.01)0.0310
Clinical benefit response rate, % (95% CI)85%
(81.2 - 88.1)
70%
(63.8 - 76.2)
2.39
(1.58 - 3.59)< 0.0001
Patients with measurable disease 338 171
Objective response rate, % (95% CI)55%
(49.9 - 60.7)
44%
(36.9 - 52.2)
1.55
(1.05 - 2.28)0.0132
Clinical benefit response rate, % (95% CI)84%
(80.0 - 88.0)
71%
(63.3 - 77.5)
2.23
(1.39 - 3.56)0.0003
Palbociclibe + Letrozol(n = 444)
Placebo + Letrozol(N = 222)
Qualquergrau
Grau 3 Grau 4Qualquer
GrauGrau 3 Grau 4
Qualquer EC, % 99 62 14 95 22 2
Neutropenia 80 56 10 6 1 < 1
Leucopenia 39 24 1 2 0 0
Anemia 24 5 < 1 9 2 0
Trombocitopenia 16 1 < 1 1 0 0
Finn R, et al. N Engl J Med 375: 1925, 2016
Neutropenia febril 1%
PALOMA-2: Mielossupressão
MONALEESA-2
MONALEESA-2: Phase III ribociclib + letrozole in HR+, HER2– ABC1,2
ABC, advanced breast cancer; CBR, clinical benefit rate; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors.1. Hortobagyi GN et al. N Engl J Med 2016;375:1738–1748; 2. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral).
R 1:1
Stratified by the presence/absence of liver and/or lung
metastases
Ribociclib (600 mg/day)3-weeks-on/1-week-off
+Letrozole (2.5 mg/day)
n=334
Placebo+
Letrozole (2.5 mg/day)n=334
• Postmenopausal
women with HR+,
HER2– ABC
• No prior therapy for
advanced disease
• N=668
Primary endpoint• PFS (locally assessed per RECIST v1.1)
Secondary endpoints• OS (key)• ORR• CBR• Safety• QoL
• Tumor assessments were performed every 8 weeks for the first 18 months, then every 12 weeks thereafter
• Final analysis planned after 302 PFS events
– 93.5% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%
• Interim analysis planned after ~70% PFS events
– Two-look Haybittle–Peto stopping criteria: hazard ratio ≤0.56 and p<0.0000129
• At the interim analysis data cut-off date (Jan 29, 2016), 243 PFS events had occurred (80% information fraction)
PFS (Investigator Assessment)
Ribociclib + Letrozole
n=334
Placebo + Letrozole
n=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
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 + Letrozole 334 294 277 257 240 226 164 119 68 20 6 1 0Placebo + Letrozole 334 279 264 237 217 192 143 88 44 23 5 0 0
Pro
ba
bility
of
PFS (
%)
0
20
40
60
80
100
0 4 8 12 16 20 24Time (months)
CI, confidence interval; NR, not reached; PFS, progression-free survival.
1. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral).
Primary endpoint was met early
MONALEESA-2: Efficacy1
*Excludes patients who had received tamoxifen.
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; ET, endocrine therapy; EXE, exemestane;
NSAI, non-steroidal aromatase inhibitor; PgR, progesterone receptor; PgR+, PgR-positive; PS, performance status.
1. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral).
Subgroup n (%) Hazard ratio (95% CI)
All patients 668 (100) 0.556 (0.429–0.720)
Age<65 years ≥65 years
373 (56)295 (44)
0.523 0.608
(0.378–0.723)(0.394–0.937)
RaceAsian
Non-Asian51 (7.6)568 (85)
0.387 0.607
(0.166–0.906)(0.459–0.804)
ECOG PS01
407 (61)261 (39)
0.588 0.528
(0.422–0.820)(0.348–0.801)
ER/PgR statusER+ and PgR+
Other546 (82)122 (18)
0.616 0.358
(0.461–0.823)(0.198–0.647)
Liver or lung involvementNoYes
295 (44)373 (56)
0.547 0.569
(0.360–0.832)(0.409–0.792)
Bone-only diseaseNoYes
521 (78)147 (22)
0.541 0.690
(0.405–0.723)(0.381–1.249)
De novo diseaseNoYes
441 (66)227 (34)
0.603 0.448
(0.447–0.814)(0.267–0.750)
Prior (neo)adjuvant ET
NSAI and others*Tamoxifen or EXE
None
53 (7.9)293 (44)322 (48)
0.448 0.570 0.570
(0.193–1.038)(0.393–0.826)(0.380–0.854)
Prior (neo)adjuvant chemotherapyNoYes
377 (56)291 (44)
0.548 0.548
(0.373–0.806)(0.384–0.780)
Favors Placebo + Letrozole
Favors Ribociclib+ Letrozole
0.5560,1 1 10
0.556
MONALEESA-2: Efficacy1
PFS benefit maintained across subgroups
• OS data were immature at the cut-off date for interim analysis
CBR in patients with measurable disease: 80% ribociclib arm vs. 72% placebo arm (p=0.02)
Ribociclib + Letrozole
Placebo + Letrozole41
28
0
20
40
60
80
100
All patients
p=0.000155
Ra
te (
%)
ORR
53
37
0
20
40
60
80
100
Patients with measurable disease
p=0.00028
Ra
te (
%)
ORR
CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival.
1. Hortobagyi GN et al. N Engl J Med 2016;375:1738–1748; 2. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral);
3. André F et al. EORTC-NCI-AACR 2016; abstr LBA 3552 (poster).
MONALEESA-2: Efficacy1,2
Ribociclib demonstrated superior ORR and CBR
MONARCH 3: Study Design
N = 493• HR+, HER2- ABC
• Postmenopausal
• Metastatic or lacally
recurrent disease with no
prior systemic therapy in this
setting
• If neoadjuvant or adjuvante
ET administered, a disease
free interval of > 12 months
since completion of ET
• ECOG PS ≤ 1 Ra
nd
om
iza
tio
n
2:1abemaciclib: 150 mg BID
(continuous schedule) plus
anastrozole: 1 mg ora
letrozole: 2.5 mg QD until PD
placebo: BID
(continuous schedule) plus
anastrozole: 1 mg ora
letrozole: 2.5 QD until PD
Primary endpoint:
Investigator-assessed PFS
Secondary endpoint:
OS, response rates, Safety
Stratification factors:
• Metastatic site (visceral,
boné only, or other
• Prior ET (AI, no ET, or other)
aper physiocian’s choice: 79.1% received letrozole, 19.9% received anastrozole
Statistics: Study powered to 80%at one-sided alpha of 0.025 assuming a hazard ratio of 0.67 with analyses at 189
and 240 PFS events. Positive study at the interim required a hazard ratio < 0.56 and two-sided p < 0.0005.
Enrollment: From November 2014 to November 2015 patients enrolled in 158 centers from 22 countries
Median follow-up: 17.8 months (interim analysis)
Patient and Disease Characteristics
Abemaciclib + NSAIn = 328
placebo + NSAIn = 165
Median age (range) 63 (38 - 87) 63 (32 - 88)
RaceCaucasianAsianOther
186 (56.7)103 (31.4)
11 (3.4)
102 (61.8)45 (27.3)
7 (4.2)
Measurable diseaseYesNo
267 (81.4)61 (18.6)
130 (78.8)35 (21.2)
Disease settingLocorregional recurrentMetastatic recurrentDe novo metastatic
11 (3.4)182 (55.5)135 (41.2)
5 (3.0)99 (60.0)61 (37.0)
Metastatic siteVisceralBone-onlyOther
172 (52.4)70 (21.3)86 (26.2)
89 (53.9)39 (23.6)37 (22.4)
Prior neoadjuvant or adjuvante chemotherapyYesNo
125 (38.1)203 (61.9)
66 (40.0)99 (60.0)
Prior neoadjuvant or adjuvante endocrine therapyNo endocrine therapyAromatase Inhibitor therapyOther endocrine therapy
178 (54.3)85 (25.9)65 (19.8)
85 (51.5)50 (30.3)30 (18.2)
Treatment free intervala36 months≥ 36 monthsUnknown
42/150 (28.0)94/150 (62.7)14/150 (9.3)
32/80 (40.0)40/80 (50.0)8/80 (10.0)
aTreatment-free interval calculated only for patients with prior endocrine therapy
Primary Endpoints (PFS) met at Interin Analysis
10
20
30
40
50
60
70
80
90
100
4 8 1 2 1 6 2 0 2 4 28
Log-rank P value = .000021
HR (95% CI): 0.54 (0.41 to 0.72)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
No. at risk:
32 8 27 1 23 4 20 5 12 5 2 5 1 0
16 5 12 7 10 5 82 4 5 7 0 0
Abemaciclib arm
Placebo arm
Abemaciclib arm: median, not reached
Placebo arm: median, 14.7 months
Censored observations
0
PFS benefit confirmed by blinded independente central review: HR (95% CI): 0.508 (0.359, 0.723); p = 0.000102
Key Secondary Endpoints
abemaciclib + NSAI placebo + NSAI p value
All patients, n 328 165 0.002
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Clinical Benefit Rate, % (95% CI)
48.2 (42.8, 53.6)
5 (1.5)
78.0 (73.6, 82.5)
34.5 (27.3, 41.8)
0
71.5 (64.6, 78.4) 0.101
Patients with measurable diseaseat
baseline, n267 130
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Clinical Benefit Rate, % (95% CI)
59.2 (53.3, 65.1)
5 (1.9)
79.4 (74.5, 84.3)
43.8 (35.3, 52.4)
0
69.2 (61.3, 77.2)
0.004
0.024
Overall Survival• OS immature at this time (49 events at cutoff)
• Final analysis will occur after 315 events
PFS: Preplanned Subgroup Analysis (ITT)
24201612840
10
20
30
40
50
60
70
80
90
100
HR (95% CI): 0.48 (0.25 to 0.91)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
Abemaciclib + NSAI: not reached
Placebo + NSAI: 9.0 months
0
Abemaciclib + NSAI: not reached
Placebo + NSAI: not reached
10
20
30
40
50
60
70
80
90
100
4 8 1 2 1 6 2 0 2 4 28
HR (95% CI): 0.83 (0.46 to 1.52)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
Exploratory PFS Analysis: Treatment-free Interval (TFI)
TFI < 36 months TFI ≥ 36 months
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 42) 77.5% 64.8% 53.0%
placebo (n = 32) 58.6% 37.9% 30.3%
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 94) 82.4% 73.7% 59.4%
placebo (n = 40) 83.5% 66.2% 53.9%
MONALEESA-2: Exploratory Analysis
Janni et al. Breast Cancer Res Treat Epub ahead of print Feb 5, 2018
Exploratory PFS Analysis: Bone-only Disease
Patients with bone-only disease Patients without bone-only disease
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 70) 87.6% 86.0% 76.5%
placebo (n = 39) 94.6% 75.7% 57.6%
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 258) 82.7% 69.5% 57.5%
placebo (n = 126) 68.4% 49.9% 35.4%
Abemaciclib + NSAI: not reached
Placebo + NSAI: not reached
10
20
30
40
50
60
70
80
90
100
0 4 8 1 2 1 6 2 0 24
HR (95% CI): 0.58 (0.27 to 1.25)
Prog
ress
ion-
Free
Surv
ival
(%)
Time (months)
Abemaciclib + NSAI: not reached
Placebo + NSAI: 11.7 months
10
20
30
40
50
60
70
80
90
100
0 4 8 1 2 1 6 2 0 2 4 28
HR (95% CI): 0.51 (0.38 to 0.70)
Prog
ress
ion-
Free
Surv
ival
(%)
Time (months)
Exploratory PFS Analysis: Liver Metastases
Patients with liver metastases Patients without liver metastases
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 48) 71.8% 61.5% 35.3%
placebo (n = 30) 53.8% 31.4% 21.5%
Landmark PFS Rate
Arm 6 months 12 months 18 months
abemaciclib (n = 280) 85.6% 74.8% 64.9%
placebo (n = 135) 78.7% 60.7% 43.9%
Abemaciclib + NSAI: 15.0 months
Placebo + NSAI: 7.2 months
10
20
30
40
50
60
70
80
90
100
0 4 8 1 2 1 6 2 0 24
HR (95% CI): 0.47 (0.25 to 0.87)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
Abemaciclib + NSAI: not reached
Placebo + NSAI: 15.4 months
10
20
30
40
50
60
70
80
90
100
0 4 8 1 2 1 6 2 0 2 4 28
HR (95% CI): 0.57 (0.41 to 0.78)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
abemaciclib + NSAI
n = 327
placebo + NSAI
n = 161
Grade, n (%) Any 2 3 4 Any 2 3 4
Any adverse event 322 (98.5) 111 (33.9) 159 (48.6) 21 (6.4) 145 (90.1) 61 (37.9) 32 (19.9) 3 (1.9)
Diarrhea 266 (81.3) 89 (27.2) 31 (9.5) 0 48 (29.8) 11 (6.8) 2 (1.2) 0
Neutropenia 135 (41.3) 53 (16.2) 64 (19.6) 5 (1.5) 3 (1.9) 1 (0.6) 1 (0.6) 1 (0.6)
Fatigue 131 (40.1) 55 (16.8) 6 (1.8) - 51 (31.7) 20 (12.4) 0 -
Nausea 126 (38.5) 36 (11.0) 3 (0.9) - 32 (19.9) 1 (0.6) 2 (1.2) -
Abdominal pain 95 (29.1) 21 (6.4) 4 (1.2) - 19 (11.8) 4 (2.5) 2 (1.2) -
Anemia 93 (28.4) 45 (13.8) 19 (5.8) 0 8 (5.0) 2 (1.2) 2 (1.2) 0
Vomiting 93 (28.4) 26 (8.0) 4 (1.2) 0 19 (11.8) 3 (1.9) 3 (1.9) 0
Alopecia 87 (26.6) 5 (1.5) - - 17 (10.6) 0 - -
Decreased appetite 80 (24.5) 26 (8.0) 4 (1.2) 0 15 (9.3) 2 (1.2) 1 (0.6) 0
Leukopenia 68 (20.8) 31 (9.5) 24 (7.3) 1 (0.3) 4 (2.5) 1 (0.6) 0 1 (0.6)
Treatment-emergent Adverse Events
(Safety Population) ≥ 20% Occurrence
• 1 patient experinced non-serious febrile neutropenia in the abemaciclib arm.• Venous thromboembolic events ocuured in 16 (4.9%) of patients in the abemaciclib arm versus 1 (0.6%) in the placebo arm
Uso de Inibidor de CDK 4/6 na primeira linha, SLP
Estudo PALOMA-1 PALOMA-2 MONALEESA-2 MONARCH-3
DesenhoFase II
randomizadoFase III
randomizadoFase III
randomizadoFase III
randomizado
HT Letrozol Letrozol LetrozolAnastrozol ou
Letrozol
N 165 666 668 493
HR para SLP 0,49 0,58 0,56 0,54
iCDK4/6 na Primeira Linha na
Pré-Menopausa
First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in
premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the
randomized Phase III MONALEESA-7 trial
Debu Tripathy,1 Joohyuk Sohn,2 Seock-Ah Im,3 Marco Colleoni,4 Fabio Franke,5 Aditya Bardia,6 Nadia Harbeck,7
Sara Hurvitz,8 Louis Chow,9 Keun Seok Lee,10 Saul Campos-Gomez,11 Rafael Villanueva Vazquez,12 Kyung Hae Jung,13
Gary Carlson,14 Gareth Hughes,15 Ivan Diaz-Padilla,15 Caroline Germa,14 Samit Hirawat,14 Yen-Shen Lu16
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2Severance Hospital of Yonsei University Health System, Seoul, Republic of Korea;3Seoul National University College of Medicine, Seoul, Republic of Korea; 4Unità di Ricerca in Senologia Medica – Istituto Europeo di Oncologia, Milan, Italy; 5Hospital de Caridade de Ijuí, CACON, Ijuí, Brazil; 6Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; 7Breast Center, University of Munich (LMU), Munich, Germany; 8UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; 9Organisation for Oncology and Translational Research, Hong Kong; 10Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; 11Centro Oncológico Estatal, Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Mexico; 12Institut Català d’Oncologia, Hospital Moisès Broggi, Barcelona, Spain; 13Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 14Novartis Pharmaceuticals Corporation, East Hanover, NJ; 15Novartis Pharma AG, Basel, Switzerland; 16National Taiwan University Hospital, Taipei, Taiwan
GS2-05
MONALEESA-7: Phase III placebo-controlled study of ribociclib
and tamoxifen/NSAI + goserelin
• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter
• Primary analysis planned after ~329 PFS events
– 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an
increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of
660 patients
NSAI, non-steroidal aromatase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors.*Tamoxifen = 20 mg/day; NSAI: anastrozole = 1 mg/day or letrozole = 2.5 mg/day; goserelin = 3.6 mg every 28 days;
‡PFS by Blinded Independent Review Committee conducted to support the primary endpoint.1. Klijn JG, et al. J Clin Oncol 2001;19:343–353; 2. Mourisden H, et al. J Clin Oncol 2001;19:2596–2606.
Stratified by:
• Presence/absence of liver/lung
metastases
• Prior chemotherapy for advanced
disease
• Endocrine therapy partner
(tamoxifen vs NSAI)
Primary endpoint
• PFS (locally assessed per RECIST v1.1)‡
Secondary endpoints
• Overall survival (key)
• Overall response rate
• Clinical benefit rate
• Safety
• Patient-reported outcomes
• Pre/perimenopausal women with HR+, HER2–
ABC
• No prior endocrine therapy for advanced disease
• ≤1 line of chemotherapy for advanced disease
• N=672
Randomization (1:1)
Ribociclib(600 mg/day; 3-weeks-on/1-
week-off)
+ tamoxifen/NSAI + goserelin*
n=335
Placebo+ tamoxifen/NSAI +
goserelin* n=337
Key enrollment criteria
• Pre/perimenopausal women (per
NCCN guidelines)
• ≥1 measurable lesion (RECIST 1.1)
or ≥1 predominantly lytic bone lesion
• ECOG performance status of ≤1
• ≤1 line of chemotherapy for ABC
• Prior (neo)adjuvant therapy was
allowed:– If no prior endocrine therapy OR if ≥12 months since the
last dose, patient was eligible for tamoxifen or
an NSAI, per investigator/patient choice
– If last dose of tamoxifen was <12 months prior to
randomization, patient was eligible for an NSAI
– If last dose of AI/NSAI was <12 months prior to
randomization, patient was eligible for tamoxifen AI, aromatase inhibitor; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; NCCN, National Comprehensive Cancer Network; QTcF, Fridericia’s corrected QT interval.
Perimenopausal defined as neither premenopausal nor postmenopausal per NCCN guidelines.Goserelin included in all combinations.
• Any prior endocrine therapy for ABC
• Inflammatory breast cancer
• Active cardiac disease or history of
cardiac
dysfunction, including QTcF >450
msec
• CNS metastases
• Symptomatic visceral disease
Key exclusion criteria Key inclusion criteria
672 patients randomized between December 2014 and August 2016Data cut-off date: August 20, 2017 (318 events)Median time from randomization to data cut-off date: 19.2 months
Accrual and analysis details
Goserelin included in all combinations.
+ Tamoxifen n=90
+ NSAI n=248
Full analysis set
Safety set
+ Tamoxifen n=87
+ NSAI n=247
Ribociclib Placebo
Received treatment
n=335
Received treatment
n=337
Patient demographics and baseline characteristics
Characteristic*Ribociclib + tamoxifen/NSAI
n=335
Placebo + tamoxifen/NSAI
n=337
Median age, years (range) 43 (25–58) 45 (29–58)
Race
Caucasian 187 (55.8) 201 (59.6)
Asian 99 (29.6) 99 (29.4)
Other‡ 29 (8.7) 19 (5.6)
Unknown 20 (6.0) 18 (5.3)
ECOG performance status§
0 245 (73.1) 255 (75.7)
1 87 (26.0) 78 (23.1)
Missing 3 (0.9) 3 (0.9)
Metastatic sites
Visceral disease 193 (57.6) 188 (55.8)
Bone-only disease 81 (24.2) 78 (23.1)
De novo metastatic disease 136 (40.6) 134 (39.8)
Non-de novo metastatic disease 199 (59.4) 203 (60.2)
Disease-free interval
≤12 months 23 (6.9) 13 (3.9)
>12 months 176 (52.5) 190 (56.4)
Prior (neo)adjuvant endocrine therapy 127 (37.9) 141 (41.8)
Prior chemotherapy
For advanced disease 47 (14.0) 47 (13.9)
(Neo)adjuvant only 138 (41.2) 138 (40.9)
None 150 (44.8) 152 (45.1)
*All values are n (%), unless stated otherwise; ‡‘Other’ includes Black, Native American, and other;§One patient in the placebo arm had an ECOG performance status of 2.
Goserelin included in all combinations.
Subgroup n (%) Favors ribociclib Favors placebo Hazard ratio 95% CI
All patients 672 (100) 0.553 0.441–0.694
Endocrine therapy
partner
Tamoxifen
NSAI
177 (26)
495 (74)
0.585
0.569
0.387–0.884
0.436–0.743
Age<40 years
≥40 years
186 (28)
486 (72)
0.443
0.590
0.293–0.671
0.449–0.777
Race‡ Asian
Non-Asian198 (29)
413 (61)0.401
0.6570.258–0.625
0.492–0.877
ECOG performance status§0
≥1
500 (74)
166 (25)
0.549
0.495
0.417–0.721
0.320–0.765
ER/PgR statusER+ and PgR+
Other
572 (85)
100 (15)
0.574
0.444
0.446–0.739
0.258–0.765
Liver and/or lung involvementNo
Yes329 (49)
343 (51)0.642
0.5030.454–0.907
0.375–0.677
Bone-only diseaseNo
Yes
513 (76)
159 (24)
0.533
0.703
0.415–0.686
0.414–1.194
Prior chemotherapy for advanced
disease
No
Yes
578 (86)
94 (14)
0.566
0.547
0.443–0.724
0.314–0.954
Disease-free interval
≤12
months
>12
months
De novo
36 (5)
366 (54)
270 (40)
0.560
0.615
0.428
0.210–1.490
0.455–0.832
0.287–0.640
PFS subgroup analysis*
ER, estrogen receptor; PgR, progesterone receptor.*Locally assessed PFS; ‡Non-Asian race includes Caucasian, Black, and Native American;
§ECOG performance status missing for n=6; 1 patient had an ECOG performance status of 2.
0.125 0.25 0.5 1 2 4
Hazard ratio (95% CI)
8
Secondary endpoints
CBR, clinical benefit rate.CBR = complete response + partial response + (stable disease + non-complete response/non-progressive disease ≥24 weeks).
Goserelin included in all combinations.
Ribociclib + tamoxifen/NSAI
Placebo + tamoxifen/NSAI
• The CBR in patients with measurable disease was 79.9% for ribociclib + tamoxifen/NSAI vs 67.3% for placebo + tamoxifen/NSAI (p=0.000340)
• Overall survival data were immature at the cut-off date
40,9
29,7
0
20
40
60
80
100
Overall response rate
All patients
Ra
te (
%)
50,9
36,4
0
20
40
60
80
100
Overall response rate
Patients with measurable disease
Ra
te (
%)
p=0.00098p=0.000317
iCDK4/6 na Segunda ou mais Linhas
• PALOMA-3
• MONARCH-2
• TREND
• MONARCH 1
Turner NC, et al. NEJM. 2015;373(3):209-219.
521 pacientesMulheres pré ou pós-menopausa ≥ 18 anos
Ca de Mama Avançado RE+ e HER2- que recidivou ou progrediu durante Terapia Endócrina prévia
Randomização 2:1Estratificação: Local da doença (visceral vs. Não visceral)
Sensibilidade à terapia endócrina prévia (sim vs. Não)
Palpociclib (125mg VO por 21 dias, com 7 dias de
intervalo)
+
Fulvestranto (500mg a cada 14 dias nas primeiras 3
doses e depois manter a cada 28 dias)
Placebo (por 21 dias, com 7 dias de intervalo)
+
Fulvestranto (500mg a cada 14 dias nas
primeiras 3 doses e depois manter a cada
28 dias)
Avaliação da doença a cada 8 semanas ± 7 dias da data da randomização
Cintilografia óssea ao screening e subsequentemente como clinicamente indicado ou para confirmar resposta completa
PALOMA-3: Estudo de Fase 3 de Fulvestrant ± Palbociclibe em Pacientes com Ca de Mama Avançado com RE+, HER2- após Progressão à Terapia Endócrina Prévia
PALOMA-3: Sobrevida Livre de Progressão com Fulvestranto ± Palbociclibe
Após Progressão à Terapia Endócrina Prévia na População Geral
Turner NC, et al. NEJM. 2015;373(3):209-219.
Tempo, meses
Pro
bab
ilid
ade
de
Sob
revi
da
Livr
e d
e P
rogr
essã
o, %
Avaliação pelos investigadores
Uso de Inibidor de CDK 4/6 na segunda linha: MONARCH 2
N = 669• HR+/HER2- ABC
• Pre/peri-a or Postmenopausal
• ET resistant:• Relapsed on
neoadjuvant or on/within 1 yr of adjuvante ET
• Progressed on first-line ET
• No chemo for MBC
• No more than 1 ET for MBC
• ECOG PS ≤ 1
Ra
nd
om
iza
tio
n
2:1 abemaciclib: 150 mgb BID
(continuous schedule)
fulvestrant: 500 mgc
placebo: BID
(continuous schedule)
fulvestrant: 500 mg orc
letrozole: 2.5 QD until PD
Primary endpoint:
Investigator-assessed PFS
Secondary endpoint:
OS, response rates, Clinical
benefit rate, safety
Stratification factors:
• Metastatic site
• ET resistant
• (primary vs secondary)4,5
aRequired to receive GnRH agonistbDose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg BID after 178 patients enrolledcFulvestrant administered per label
Statistics: 378 events for 90% power at one-sided a of .025 assuming a true HR of .703
Patients enrolled in 142 centers in 19 countries
Study design
4. Cardoso F et al. The Breast 8:489-502, 2014; 5. Cardoso F et al. Ann Oncol 25: 1571-88, 2014
ASCO 2017
Uso de Inibidor de CDK 4/6 na segunda linha: MONARCH 2
Primary Endpoint: PFS (ITT)
PFS benefit confirmed by blinded independente central review
(HR: .460; 95% CI: .363, .584; P < .000001
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27 30
Time (months)Patients at risk:
abemaciclib
placebo446
223
367
165
314
123
281
103
234
80
171
61
101
32
65
13
32
4
2
1
0
0
Median PFSabemaciclib + fulvestrant: 16.4 months
placebo + fulvestrant: 9.3 months
HR (95% CI): .553 (.449, .681)P < .0000001
Pro
gre
ssio
n-f
ree
su
rviv
al (
%)
Presented by Luca Malorni at ASCO 2017
TREnd study design
• Post-menopausal ER+/HER2-
mBC
• Pre-treated with 1 or 2 lines of
ET for mBC
• 1 prior line of CHT for mBC
permitted
• FFPE tumor available for
biomarkers
Key eligibility criteria:R
A
N
D
O
M
I
Z
A
T
I
O
N
Palbociclib 125 mg/d3w on/1w off
Palbociclib 125 mg/d3w on/1w off
+
same ET as pre-progression
(Aromatase inhibitor or Fulvestrant)
1:1
Stratification Factors:Disease site (visceral vs other)Number of prior lines of ET for mBC (1 vs. 2)Duration of prior line of ET for mBC (> 6 vs ≤ 6 months)
N = 115
TREnd trial
Primary Endpoint: Clinical Benefit Rate
Presented by Luca Malorni at ASCO 2017
P + ET
N = 57
P
N = 58
Clinical Benefit Rate, n (%)
95% C.I.
31 (54%)
41.5; 63.7
35 (60%)
47.8; 72.9
CR 0 (0%) 0 (0%)
PR 6 (10%) 4 (7%)
SD ≥ 24 weeks 25 (44%) 31 (53%)
MONARCH 1 (abemaciclibe como agente único)
Dickler et al. Clin Cancer Res 23:5218, 2017
• N=132 pacientes
• 90% com envolvimento visceral
• Refratários a várias linhas de tratamento
• Abemaciclibe com agente único
• RG 19,7%
• Duração mediana de resposta 8,6 mses
QT vs HT na Primeira Linha: Dados de Eficácia
*Lam et al. Eur J Cancer 50:3077, 2014
Letrozol + Palbo Letrozol isolado Pacli + Cape + Bev* Pacli + Bev
TRG 55,3% 44,4% 69% 51%
TLP 24,9 meses 14,5 meses 11,2 meses 8,4 meses
Take Home Message
• iCDK4/6 em combinação com IA na primeira linha aumenta TLP e
resposta quando comparado com IA isolado tanto na pós-
menopausa quando na pre-menopausa (que é colocada em pós-
menopausa por supressão ovariana).
• Na segunda ou mais linhas iCDK4/6 em combinação com
Fulvestranto aumenta TLP em relação a Fulvestranto isolado.
• Taxa de resposta de iCDK4/6 + IA na primeira linha é da ordem de
50 a 60% com TLP da ordem de 2 ou mais anos (mais durável que
qualquer esquema de QT na primeira linha).
Algoritmo de Manejo
Sem HT prévia (adjuvante ou para doença metastática)
Com HT prévia
Fulvestranto ou IA+iCDK4/6
Com doença visceral*
*mas sem crise visceral
IA + iCDK4/6 Fulvestranto + iCDK4/6
Doença metastática RH+ HER2- Primeira linha(mulheres na pre-menopausa deve ser transformadas em pós-menopausadas com SO)
Recorrência durante ou nos primeiros 12 meses após
completar a adjuvância com IA
IA + iCDK4/6
Recorrência durante ou após Tam ou >12 meses
do IA na adjuvância
Sem envolvimeto
visceral
IA isolado pode ser considerado em casos com doença pouco agressiva e de grande hormônio-sensibilidade: ILD muito prolongado (muitos anos
após completada a adjuvância), doença limitada oligo-sintomática ou assintomática de baixo volume, idade avançada, metástases predominantemente
ósseas ou ganglionares, etc.
NOTA: Mulheres Pré-menopáusicas que
venham a receber IA devem ter a função
ovariana bloqueada
Thank you