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(1)

Actualización en cáncer de mama avanzado luminal:

de la práctica clínica a los nuevos fármacos

Dr. Ricardo Fernández Oncología Médica.

Instituto Oncológico IMQ Bilbao. Clínica IMQ Zorrotzaurre. Bilbao.

r.fernandez@imq.es Con el patrocinio de:

Organizada por:

10 de mayo de 2017

Hotel Hesperia Bilbao

Inhibidores de Ciclinas:

Estudios en Marcha,

Futuros y en Otras

Indicaciones

(2)

Hallmarks of Cancer: Evadir los supresores del crecimiento

(3)

Las ciclinas y la regulación del ciclo celular

La inhibición de CDK4/6 reduce la proliferación celular en cáncer de

mama resistente a HT

Las ciclinas son las principales

proteínas encargadas de la regulación

del ciclo celular y actúan regulando la

actividad de las quinasas dependientes

de ciclinas o CDKS

CD1, que activa CDK4 y CDK6, está

amplificada en un 15-20% de los casos

de cáncer de mama

La interacción de la ciclina D1 con la

CDK4 y 6, facilita la hiperfosforilación

de la proteína del retinoblastoma que

promueve la progresión de la Fase G1

del ciclo celular a Fase S

CDK4-6 están sobreactivadas en numerosos cánceres produciendo pérdida del control de la proliferación.

(4)

Inhibidores de ciclinas

Fry DW et al. Mol Cancer Ther 2004;3:1427-37 Gelbert LM et al. Invest New Drugs 2014;32:825-37 Rader et al. Clin Cancer Res 2013;19:6173-82

Actividad muy potente incluso en los tumores resistentes a HT Buen perfil de toxicidad (neutropenia, diarrea)

(5)

Ensayos en marcha con inhibidores de ciclinas

Neo

Adjuvant

Adjuvant

First line

Second

line

Third

line

Guideline-recommended endocrine therapies • AIs • TAM Trials of interest • UNIRAD (EVE) • PENELOPE-B PALLAS • EarLEE-1 • EarLEE-2 Guideline-recommended endocrine therapies

• FUL, AIs, TAM

• EVE+EXE Trials of interest • BOLERO-4 • PALOMA-2 • MONALEESA-2 • MONALEESA-7 (pre) PATRICIA PARSIFAL FLIPPER MONARCH-2 MONARCH-3 Guideline-recommended endocrine therapies

• AIs, TAM, FUL

• EVE+EXE Trials of interest • BOLERO-6 • BELLE-2 (BKM) • PALOMA-3 • PEARL MONALEESA-3 • MONARCH-1 • MONARCH-2 Guideline-recommended endocrine therapies

• AIs, TAM, FUL

• EVE+EXE Trials of interest • BOLERO-6 • BELLE-3 (BKM) • PEARL

Abbreviations: AI, aromatase inhibitor; EVE, everolimus; EXE, exemestane; FUL, fulvestrant; TAM, tamoxifen

Guideline-recommended • AIs • TAM • CT Trials of interest NeoPalAna • MONALEESA-1 • FELINE

(6)
(7)
(8)

Palbociclib + Letrozol vs. Letrozol alone as

1st line in ER+/HER2- MBC (PALOMA-1)

(9)

PALOMA 2: Objetivo Primario

SLP

Palbociclib+let N=444 Placebo + let N=222 SLP mediana 24.8 m 14.5 m

HR 0.58; IC 95% (0.46-0.72); p-value one side:< 0.0001

Finn R et al. N Engl J Med 2016; 375:1925-1936November 17, 2016.DOI: 10.1056/NEJMoa1607303

Multicenter, international, double-blind, randomized phase III trial

Postmenopausal women with ER+/HER2- advanced

breast cancer, no prior treatment for advanced disease, no

Al resistance (N = 666)

Stratified by disease site (visceral vs nonvisceral),

disease-free interval (de novo metastatic; ≤ 12 mos vs > 12 mos), prior neoadjuvant or adjuvant hormonal therapy (yes vs no)

Palbociclib 125 mg QD (3/1 schedule) + Letrozole 2.5 mg QD (n = 444) Placebo (3/1 schedule) + Letrozole 2.5 mg QD (n = 222)

(10)

PALOMA-2: Conclusiones

Palbociclib + letrozol en primera línea mejoró significativamente la

PFS mediana versus placebo + letrozol en mujeres con cáncer de

mama avanzado ER + / HER2

Median PFS mejoró > 10 m comparado con placebo

24.8 vs 14.5 mos, HR: 0.58 (95% CI: 0.46-0.72;

P

< .0001)

Beneficio clínico observado en todos los subgrupos preespecificados

Palbociclib bien tolerado con neutropenia, leucopenia los EA más

frecuentemente reportados

Los datos de PALOMA-2 [1] confirman los resultados de PALOMA-1

[2] y constituyen la PFS más larga hasta la fecha en 1 línea de cáncer

de mama ER + avanzado

Finn R, et al. ASCO 2016. Abstract 507. Finn R et al. N Engl J Med 2016; 375:1925-1936November 17, 2016.DOI: 10.1056/NEJMoa1607303

(11)

2 100 80 60 40 20 0 0 4 6 8 10 12 14

Median PFS, Mos (95% CI)

Fulvestrant + palbociclib (n = 347): 9.5 (9.2-11.0) Fulvestrant + placebo (n = 174): 4.6 (3.5-5.6) HR: 0.46 (95% CI: 0.36-0.59; P = .0001) PF S (% ) Mos

Median follow-up: 8.9 mos

Median PFS generally favored the palbociclib combination in all pt subgroups analyzed

Cristofanilli M, et al. Lancet Oncol. 2016;17:425-439.

PALOMA-3: PFS in Overall Population

• Primary endpoint: PFS

• Secondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported

outcomes, safety

Pts with HR+/HER2- MBC; PD after endocrine therapy; ≤ 1 chemotherapy regimen for advanced BC

(N = 521) Palbociclib 125 mg QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W* (n = 347) Treatment to PD, toxicity, study withdrawal, or death Placebo QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W* (n = 174)

Stratified by visceral metastases (yes/no), sensitivity to previous endocrine therapy, menopausal status

(12)
(13)

100 50 20 0 -30 -50 -100 Ch an ge From Ba seline (%) PD (n = 34) SD (n = 63) PR (n = 26) Not assessed (n = 9) Investigator Assessed Response* Abemaciclib 200 mg (N = 132)

Confirmed ORR, % (95% CI) 19.7 (13.3-27.5)

 CR, % 0

 PR, % 19.7

SD ≥ 6 mos 22.7 CBR (CBR = ORR + SD ≥ 6 mos) 42.4

Dickler MN, et al. ASCO 2016. Abstract 510.

Median time to response: 3.7 mos

Median DoR: 8.6 mos (

6-mo DoR rate: 70.4%)

Median PFS: 6.0 mos (95% CI: 4.2-7.5)

Median OS: 17.7 mos (95% CI: 16.0-NR)

Inclusion criteria (N = 132): Progression on or after endocrine therapy; ≥ 2 previous chemotherapy regimens (≥ 1 for metastatic disease and ≥ 1 with taxane; no previous treatment with CDK4/6 inh)

Phase II MONARCH 1:

Abemaciclib in Previously Treated HR+/HER2- MBC

Primary endpoint: ORR

Secondary: DoR, PFS, OS, CBR, safety

(14)
(15)

MONALEESA-2: Objetivo

primario (SLP)

Aumento en PFS estadísticamente

significativo: NR vs 14,7 m, HR = 0,556; p = 0,00000329

Beneficio en todos los subgrupos y para otros criterios de valoración secundarios • Bien tolerado, los AEs comunes 3/4 fueron

neutropenia y leucopenia

• Designación de FDA Breakthrough Therapy

RIBO en combinación con letrozol

Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-1748.

Ribociclib 600 mg/day PO

3 wks on, 1 wk off +

Letrozole 2.5 mg/day

(n = 334)

Placebo PO daily 3 wks on, 1 wk off + Letrozole 2.5 mg/day

(n = 334)

Recurrent or MBC, postmenopausal, no previous systemic therapy for advanced disease, ECOG PS 0/1

Stratified by liver/lung metastases (present/absent) No crossover allowed (N = 668)

(16)

Inhibidores de Ciclinas

en Neoadyuvancia

(17)

NeoPalAna:

Neoadjuvant palbociclib and anastrozole for

clinical stage 2 or 3 estrogen receptor positive breast cancer

50 pacientes stage II/III ER+/HER2-

Design: ANA 1 mes – PALBO+ANA –BX –si ki67<10% -- ANA solo hasta CIRUGIA y PALBO 10 dias luego (ciclo adicional)

Primary endpoint: Complete Cell Cycle Arrest (CCCA: central Ki67<2.7%).

• La tasa de CCCA fue

significativamente mayor después de la adición de palbociclib a anastrozol (C1D15 87% vs C1D1 26%, p <0,001). • El palbociclib aumentó el

control del ciclo celular sobre anastrozol solo

independientemente del

subtipo luminal (A vs B) y del estado PIK3CA

La resistencia se asoció con subtipos no luminal (por PAM50) y la expresión persistente del E2F target gene (DNA repair).

(18)

Phase 2 neoMONARCH Study Design

Rationale:

♦ Change in Ki67 at 2 weeks in

neoadjuvant studies may be predictive of improved disease-free survival in adjuvant studies.1,2

Secondary and exploratory objectives:

♦ Safety, clinical, radiologic and

pathological response, cell cycle associated gene expression. Statistical design:

♦ 220 randomized required to achieve 50 evaluable patients / arm.

♦ 80% power at one-sided alpha of 0.1, assuming:

• Assumed mean reduction of 82 % for anastrozole alone and 91% for

combination.

Post-menopausal women (N = 220) HR+, HER2- breast cancer stage: I (T ≥ 1 cm), II, IIIA or IIIB suitable for neoadjuvant endocrine therapy

Primary endpoint:

Compare the change from baseline in Ki67 expression after 2 weeks of therapy

Core biopsy at baseline

Core biopsy after 2 weeks of treatment

Abemaciclib  150 mg Q12H Anastrozole 1 mg QD Abemaciclib 150 mg Q12H + Anastrozole 1 mg QD

Core biopsy after 14 weeks of treatment b

Abemaciclib  150 mg Q12H + Anastrozole 1 mg QD

Surgery (optional) a Stratified for PR status, tumor size

b Participants who experience benefit following 14 weeks may remain on neoadjuvant therapy for up to 8 additional weeks

San Antonio Breast Cancer Symposium, December 6 - 10, 2016

1. Dowsett M et al. Clin Cancer Res 2005; 11:951s-958s.

2. Dowsett M et al. J Natl Cancer Inst. 2011a;103(22):1656-1664.

(19)

Ki67 Expression and Response at Week 2

Complete Cell Cycle Arrest

San Antonio Breast Cancer Symposium, December 6 - 10, 2016

Cha ng e from Ba s e li ne (% ) n = 54 n = 56 n = 51

a Geometric Mean Ratio (GMR), 2-sided 90 % confidence interval (CI), p-value. p-values are based on a one-sided hypothesis test from a linear model with treatment

bA responder is identified as a patient with a ln(Ki67) value of less than 1. Odds ratio (OR), 2-sided 90 % CI, p value. p value is calculated by Fisher's Exact test of a one-sided hypothesis. * Patient had received dose intensity of 19% for abemaciclib prior to Week 2 biopsy.

Geometric Mean Change

(Primary Endpoint of Study)

GMR = M e a n Cha ng e in Ki6 7 (% ) 0 -20 -40 -60 -80 -100 0.20 (0.13, 0.30) p<0.001a 0.26 (0.17, 0.38) p<0.001a - 63.2 - 92.6 - 90.6 n = 54 n = 56 n = 51

(Ki67 index <2.7% at 2 weeks)

OR = Res po ns e Rate (% ) 100 80 40 60 20 0 11.2 (4.7, 27.4) p<0.001b 14.8 66.1 58.8 Responders b: 8 37 30 8.2 (3.4, 20.2) p<0.001b Anastrozole 1 mg Abemaciclib 150 mg + Anastrozole 1 mg Abemaciclib 150 mg * 0 50 100 -100 -50

(20)

Tumor Differentiation & Immune Infiltrates Over Time

San Antonio Breast Cancer Symposium, December 6 - 10, 2016

C1D15 T Regulatory cells (FOXP3) Total T cells (CD3) Suppressor/ Cytotoxic T cells (CD8) C5D28 Baseline H&E Moderately Differentiated Ki67: 20% Well Differentiated Ki67: 3.4% Well Differentiated Ki67: 0.2% (Abemaciclib monotherapy)

(21)
(22)

MONALEESA-1 (CLEE011A2201)

Pre-surgical PD dose optimization of LEE011 in combination with letrozole

Phase II study in postmenopausal women with newly diagnosed

HR+, HER2– early BC (1st line)

Primary endpoint

Proliferation

(Ki67)

Secondary

endpoints

Safety

ECG

Changes in

biomarkers (e.g.

phospho-Rb

and CDK1)

PK

NCT01919229. 2 weeks Randomiz ation 1: 1: 1 Screening Surg ery LEE011 400 mg/day + letrozole 2.5 mg/day (n=40) Letrozole 2.5 mg/day (n=40) LEE011 600 mg/day + letrozole 2.5 mg/day (n=40) Postmenopausal patients with HR+, HER2–, early BC Resectable tumor with diameter ≥1.5cm by ultrasound Grade II–III

• Estudio cerrado por bajo reclutamiento a nivel global. En España, Vall d´Hebron y H. del Mar.

• 14 pax reclutados a nivel global (España 40%)

(23)

NA-PHER2: PALBO + FUL + PERTU + TRASTU

(24)

https://www.clinicaltrials.gov/ct2/show/NCT02712723?term=riboc

iclib+neoadjuvant&rank=1

FELINE:

Letrozole plus ribociclib or placebo as

neo-adjuvant

therapy in ER-positive, HER2-negative EBC

• Si ribociclib + letrozol durante 24 semanas como HT neoadyuvante

aumenta la proporción de mujeres con índice de pronóstico

endocrino preoperatorio (PEPI) de 0 en la cirugía en comparación

con los pacientes tratados con letrozol solo.

• Primary Outcome Measures: Rate of Pre-operative Endocrine Prognostic Index (PEPI) score 0 at surgery

• Secondary Outcome Measures:

• Rate of complete cell cycle arrest at 2 weeks between ribociclib containing arms (combined) vs letrozole alone arm: Complete cell cycle arrest is defined as Ki67 at day 14 of < 2.7% [ Time Frame: Day 14 of Cycle 1 ]

• Otros: pCR clinical complete response rate (cCR rate), 5 Year Relapse Free Survival (RFS)

(25)

Inhibidores de Ciclinas

en Adyuvancia

(26)
(27)

Enfermedad residual tras QT neo

PENELOPEB (ANZ 1402 / GBG-78 / BIG 1-13 / NSABP-B-54-I)

Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor in patients with hormone receptor positive, HER2 normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy.

(28)

Adjuvant Ribociclib With Endocrine Therapy in Hormone

Receptor+/HER2- High Risk EarlyBreast Cancer (EarLEE-1)

https://www.clinicaltrials.gov/ct2/show/NCT03078751?term=rib

ociclib+breast&rank=1

Adjuvant Ribociclib With Endocrine Therapy in Hormone

Receptor+/HER2- Intermediate Risk Early Breast Cancer (EarLEE-2)

(EarLEE-2)

https://www.clinicaltrials.gov/ct2/show/NCT03081234?term=rib

ociclib+breast&rank=2

(29)

Inhibidores de Ciclinas

más en 1ª línea

(30)

ER-HER2+ MBC patients 3-4L R A M D O M I Z A T I O N Stage I N1= 15 Stage II N2= 31 ER+HER2+ MBC patients 3-4L

INTERIM ANALISYS Stage I Go on if > 5/15 PFS6

---FINAL ANALISYS Stage I+II Efficacy if > 18/46 PFS6

---Safety Run-in phase Nr=12

Palbociclib +Trastuzumab Palbociclib +Trastuzumab + Letrozole 1:1 N1=3+12 N1= 3+12 N1= 6+9 A B1 B2 Palbociclib +Trastuzumab Palbociclib +Trastuzumab Palbociclib +Trastuzumab Palbociclib +Trastuzumab + Letrozole

PATRICIA

: Estudio fase II de la combinación de palbociclib y trastuzumab, con o sin letrozol, en pacientes postmenopáusicas con cáncer de mama metastásico HER2-positivo previamente tratado

(31)

1º línea CMM ER+

HER2-

Tratadas 5 años y

libres de

enfermedad 1 año

tras finalización

de HT adyuvante

Metastasicas de

novo

A phase II study to compare fulvestrant (F) 500mg plus placebo versus (vs) F 500mg plus palbociclib (P) as first line treatment for postmenopausal women with hormone receptor (HR)- positive advanced breast cancer (BC) sensitive to

endocrine therapy (ET). “The FLIPPER Study” (GEICAM/2014-12)

(32)

open-label, randomized, controlled, multicenter phase II clinical trial. We recruit women with ER(+)/HER2(-) LA or

MBC in first line therapy for advance disease

(33)

MONARCH-2 (Phase 3, 1st- or 2nd-Line)

Study Design

Abemaciclib (200 mg BID) + FUL (500 mg q 28 days with

loading dose during cycle 1)

Placebo +

FUL (500 mg q 28 days with loading dose during cycle 1)

Key endpoints

Primary: PFS

Secondary: OS, ORR, CBR, QOL, Safety, PK Phase 3 Study

Planned N = 550

•Postmenopausal HR+, HER2 ABC

•ECOG PS ≤ 1

•Maximum of 1 line of endocrine therapy for advanced disease

R

2:1

Abbreviations: ABC, advanced breast cancer; CBR, clinical benefit rate; ECOG, Eastern Cooperative Oncology Group; FUL, fulvestrant; HR+,

hormone receptor-positive; HER2–, human epidermal growth factor receptor-2–negative; ORR, objective response rate; OS, overall survival;

QOL, quality of life; PFS, progression-free survival; PK, pharmacokinetics.

www.clinicaltrials.gov (NCT02107703). Estimated primary completion date February 2017.

(34)

MONARCH-3 (Phase 3, 1st-Line)

Study Design

Abbreviations: ABC, advanced breast cancer; ANA, anastrozole; CBR, clinical benefit rate; ECOG, Eastern Cooperative Oncology Group; HR+, hormone receptor-positive;

HER2–, human epidermal growth factor receptor-2–negative; LET, letrozole; ORR, objective response rate; OS, overall survival; QOL, quality of life; PFS, progression-free

survival; PK, pharmacokinetics.

www.clinicaltrials.gov (NCT02246621).

Estimated primary completion date June 2017

Abemaciclib (150 mg BID) + LET (2.5 mg) or ANA (1 mg) Placebo + LET (2.5 mg) or ANA (1 mg) Key endpoints Primary: PFS

Secondary: OS, DOR, DCR, CBR, ORR, QOL, PK

Phase 3 Study Planned N = 450

(Not yet recruiting)

•Postmenopausal HR+, HER2 ABC

•ECOG PS ≤ 1

•No prior systemic therapy for ABC

R

(35)

MONALEESA-7 (Phase 3, 1

st

-line):

Ribociclib (LEE011) in Premenopausal Women

Tamoxifen / NSAI + Goserelin + Placebob Tamoxifen / NSAI + Goserelin + Ribociclib (LEE011)b Randomiz ation 1 :1

Phase 3 Trial

Planned N = 660

(estimated primary completion date: February 2018) •Premenopausal women •HR+, HER2 ABC

•No prior hormonal therapy for ABCa

•Measurable disease or 1 lytic bone lesion •ECOG PS 0/1 Primary endpoint •PFS by local assessment (RECIST v1.1) Key secondary •OS Secondary endpoints

•ORR, CBR, TTR, DoR, ECOG

PS, QoL, Safety

Stratification Factors

• Presence of liver and/or lung metastases • Prior chemotherapy for advanced disease • Endocrine therapy partner (tamoxifen vs NSAI)

a Prior endocrine therapy for advanced disease of ≤14 days of tamoxifen or nonsteroidal aromatase inhibitor ± goserelin prior to randomization is allowed.

b Ribociclib or placebo (600 mg) given once daily for 21 days followed by a 7-day break (28-day cycle).Letrozole (2.5 mg), anastrozole (1 mg), tamoxifen (20 mg) given on a continuous

dosing schedule (28-day cycles). Goserelin (3.6 mg) given on Day 1 of each 28 day cycle.

Abbreviations: ABC, advanced breast cancer; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; ET, endocrine therapy; HR+, hormone

receptor positive; NSAI, nonsteroidal aromatase inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response.

(36)

A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and

Safety of Palbociclib + HER2 therapy + Endocrine therapy vs.

Anti-HER2 therapy + Endocrine therapy after induction treatment for Hormone

Receptor Positive (HR+)/HER2-Positive MBC

PATINA

Mantenimiento antiher2 + HT +/- Palbo

(37)

Inhibidores de Ciclinas

en 2ª línea y sucesivas

(38)

Planned N = 348

Postmenopausal •HR+, HER2 MBC

refractory to prior NSAIa

•No prior treatment for advanced disease

•Measurable disease or lytic bone lesions

a Defined as recurrence while on or within 12 months after the end of adjuvant treatment or progression while on or within 1 month after the end of

treatment for advanced disease.

Palbociclib (125 mg PO daily) + Exemestane (25 mg) Capecitabine (1250 mg/m2)

Endpoints

•Primary: PFS •Secondary: ORR, CBR, RD,

OS, Safety, biomarkers (cell cycle), HRQoL

Abbreviations: CBR, clinical benefit rate; HRQoL, health-related quality of life; PFS, progression-free survival; ORR, objective response rate; OS, overall safety; RD, response duration.

Martin M, et al. ESMO 2014, Abstract 409TiP; www.clinicaltrials.gov (NCT02028507).

R 1:1

Trial start date: Mar 2014

Estimated primary completion

date

(primary data): Jan 2018

Trial status: Currently recruiting

Stratification

Visceral vs nonvisceral metastases

Prior sensitivity to hormonal treatment:

yes vs no

Prior chemotherapy for MBC: yes vs no

Country

PALBO + EXE vs CAPECITABINA

(39)

Conclusiones: Inhibidores de Ciclinas:

Estudios en Marcha, Futuros y en Otras Indicaciones

La vía ciclina D-CDK4/6-Rb es un importante mediador del ciclo celular y se

encuentra alterada en numerosas líneas tumorales. Es, por tanto, una

estrategia importante a considerar en la terapia antineoplásica.

Se están desarrollando diferentes inhibidores de CDK4/6 en combinación

con hormonoterapia y otras terapias dirigidas (antiHER2, inhibidores de la

vía PI3K/AKT/mTOR, etc.) con grandes resultados en eficacia.

Son tratamientos muy bien tolerados con un perfil de toxicidad aceptable y

manejable (neutropenia, diarrea).

Representan una buena oportunidad para revertir la resistencia a la

hormonoterapia en el cáncer de mama quedando un largo camino en su

desarrollo y posicionamiento en todos los escenarios del tratamiento del

cáncer de mama.

(40)

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