inibidor de cdk4/6 no tratamento do cancer de mama ... · paloma 1: estudo de fase ii, randomizado...

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)


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)


PALOMA-2: Objetivos Secundários


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


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


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


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


abemaciclib (n = 70) 87.6% 86.0% 76.5%

placebo (n = 39) 94.6% 75.7% 57.6%

Landmark PFS Rate


abemaciclib (n = 258) 82.7% 69.5% 57.5%

placebo (n = 126) 68.4% 49.9% 35.4%


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)



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


abemaciclib (n = 48) 71.8% 61.5% 35.3%

placebo (n = 30) 53.8% 31.4% 21.5%

Landmark PFS Rate


abemaciclib (n = 280) 85.6% 74.8% 64.9%

placebo (n = 135) 78.7% 60.7% 43.9%

Abemaciclib + NSAI: 15.0 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

(%)



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.


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).


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

inibidor de cdk4/6 no tratamento do cancer de mama ... · paloma 1: estudo de fase ii, randomizado...

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