“
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
Hallmarks of Cancer: Evadir los supresores del crecimiento
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.
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)
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
Palbociclib + Letrozol vs. Letrozol alone as
1st line in ER+/HER2- MBC (PALOMA-1)
PALOMA 2: Objetivo Primario
SLP
Palbociclib+let N=444 Placebo + let N=222 SLP mediana 24.8 m 14.5 mHR 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)
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
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
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
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)
Inhibidores de Ciclinas
en Neoadyuvancia
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).
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.
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
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)
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%)
NA-PHER2: PALBO + FUL + PERTU + TRASTU
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)
Inhibidores de Ciclinas
en Adyuvancia
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.
•
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
Inhibidores de Ciclinas
más en 1ª línea
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•
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)
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
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.
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
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.
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 +/- PalboInhibidores de Ciclinas
en 2ª línea y sucesivas
Planned N = 348
Postmenopausal •HR+, HER2– MBCrefractory 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