Inhibidores de Ciclinas: Estudios en Marcha, Futuros y en Otras Indicaciones

Transcripción

1 Actualización en cáncer de mama avanzado luminal: de la práctica clínica a los nuevos fármacos Inhibidores de Ciclinas: Estudios en Marcha, Futuros y en Otras Indicaciones Dr. Ricardo Fernández Oncología Médica. Instituto Oncológico IMQ Bilbao. Clínica IMQ Zorrotzaurre. Bilbao. r.fernandez@imq.es Con el patrocinio de: 10 de mayo de 2017 Hotel Hesperia Bilbao Organizada por:

2 Hallmarks of Cancer: Evadir los supresores del crecimiento Hanahan & Weinberg. The Hallmarks of Cancer: Next Generation. Cell 2011;144:

3 Las ciclinas y la regulación del ciclo celular 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. La inhibición de CDK4/6 reduce la proliferación celular en cáncer de mama resistente a HT

4 Inhibidores de ciclinas Actividad muy potente incluso en los tumores resistentes a HT Buen perfil de toxicidad (neutropenia, diarrea) Fry DW et al. Mol Cancer Ther 2004;3: Gelbert LM et al. Invest New Drugs 2014;32: Rader et al. Clin Cancer Res 2013;19:

5 Ensayos en marcha con inhibidores de ciclinas Neo Adjuvant Adjuvant First line Second line Third line Guidelinerecommended AIs TAM CT Trials of interest NeoPalAna MONALEESA-1 FELINE Guidelinerecommended endocrine therapies AIs TAM Trials of interest UNIRAD (EVE) PENELOPE-B PALLAS EarLEE-1 EarLEE-2 Guidelinerecommended 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 Guidelinerecommended endocrine therapies AIs, TAM, FUL EVE+EXE Trials of interest BOLERO-6 BELLE-2 (BKM) PALOMA-3 PEARL MONALEESA-3 MONARCH-1 MONARCH-2 Guidelinerecommended 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

6 Ensayos clínicos en otros tumores

7 Palbociclib

8 Palbociclib + Letrozol vs. Letrozol alone as 1st line in ER+/HER2- MBC (PALOMA-1)

9 PALOMA 2: Objetivo Primario SLP Multicenter, international, double-blind, randomized phase III trial 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) Postmenopausal women with ER+/HER2- advanced breast cancer, no prior treatment for advanced disease, no Al resistance (N = 666) 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) Palbociclib+let N=444 Placebo + let N=222 SLP mediana 24.8 m 14.5 m HR 0.58; IC 95% ( ); p-value one side:< Finn R et al. N Engl J Med 2016; 375: November 17, 2016.DOI: /NEJMoa

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: ; 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. N Engl J Med 2016; 375: November 17, 2016.DOI: /NEJMoa Finn R, et al. ASCO Abstract 507.

11 PFS (%) PALOMA-3: PFS in Overall Population Pts with HR+/HER2- MBC; PD after endocrine therapy; 1 chemotherapy regimen for advanced BC (N = 521) 100 Palbociclib 125 mg QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W* Median follow-up: 8.9 mos Median PFS, Mos (95% CI) Fulvestrant + palbociclib (n = 347): 9.5 ( ) Fulvestrant + placebo (n = 174): 4.6 ( ) HR: 0.46 (95% CI: ; P =.0001) (n = 347) Treatment to PD, 60 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 Primary endpoint: PFS Secondary endpoints: ORR, CBR (CR, PR, or SD for 24 wks), OS, pt-reported outcomes, safety Mos Median PFS generally favored the palbociclib combination in all pt subgroups analyzed Cristofanilli M, et al. Lancet Oncol. 2016;17:

12 Abemaciclib

13 Change From Baseline (%) Phase II MONARCH 1: Abemaciclib in Previously Treated HR+/HER2- MBC 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) 100 Primary endpoint: ORR Secondary: DoR, PFS, OS, CBR, safety Investigator Assessed Response * Abemaciclib 200 mg (N = 132) Confirmed ORR, % (95% CI) 19.7 ( ) CR, % PR, % 19.7 SD 6 mos 22.7 CBR (CBR = ORR + SD 6 mos) Disease control rate was 67.4% PD (n = 34) SD (n = 63) PR (n = 26) Not assessed (n = 9) -100 Dickler MN, et al. ASCO 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: ) Median OS: 17.7 mos (95% CI: 16.0-NR)

14 Ribociclib

15 MONALEESA-2: Objetivo primario (SLP) Recurrent or MBC, postmenopausal, no previous systemic therapy for advanced disease, ECOG PS 0/1 Ribociclib 600 mg/day PO 3 wks on, 1 wk off + Letrozole 2.5 mg/day (n = 334) (N = 668) Stratified by liver/lung metastases (present/absent) No crossover allowed Placebo PO daily 3 wks on, 1 wk off + Letrozole 2.5 mg/day (n = 334) Aumento en PFS estadísticamente significativo: NR vs 14,7 m, HR = 0,556; p = 0, 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:

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). Ma CX, AACR DOI: / CCR

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. 1. Dowsett M et al. Clin Cancer Res 2005; 11:951s-958s. 2. Dowsett M et al. J Natl Cancer Inst. 2011a;103(22): Post-menopausal women (N = 220) HR+, HER2- breast cancer stage: I (T 1 cm), II, IIIA or IIIB suitable for neoadjuvant endocrine therapy Anastrozole 1 mg QD Core biopsy at baseline Randomizacion Abemaciclib 150 mg Q12H + Anastrozole 1 mg QD Core biopsy after 2 weeks of treatment Primary endpoint: Compare the change from baseline in Ki67 expression after 2 weeks of therapy Abemaciclib 150 mg Q12H + Anastrozole 1 mg QD Core biopsy after 14 weeks of treatment b Surgery (optional) Abemaciclib 150 mg Q12H 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

19 Change from Baseline (%) Mean Change in Ki67 (%) Response Rate (%) Ki67 Expression and Response at Week 2 Geometric Mean Change (Primary Endpoint of Study) Complete Cell Cycle Arrest Anastrozole 1 mg 0-20 n = 54 n = 56 n = OR = 11.2 (4.7, 27.4) p<0.001 b 8.2 (3.4, 20.2) p<0.001 b Abemaciclib 150 mg + Anastrozole 1 mg Abemaciclib 150 mg GMR = 0.20 (0.13, 0.30) p<0.001 a 0.26 (0.17, 0.38) p<0.001 a Responders b : (Ki67 index <2.7% at 2 weeks) * n = 54 n = 56 n = 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. San Antonio Breast Cancer Symposium, December 6-10, 2016

20 Tumor Differentiation & Immune Infiltrates Over Time H&E Total T cells (CD3) Suppressor/ Cytotoxic T cells (CD8) T Regulatory cells (FOXP3) Baseline Moderately Differentiated Ki67: 20% C1D15 (Abemaciclib monotherapy) Well Differentiated Ki67: 3.4% C5D28 (Abemaciclib & Anastrozole) Well Differentiated Ki67: 0.2% San Antonio Breast Cancer Symposium, December 6-10, 2016

21 Curigliano G The Breast 28 (2016): 191e198

22 Screening Randomization 1:1:1 Surgery 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 (1 st line) NCT weeks Postmenopausal patients with HR+, HER2, early BC Resectable tumor with diameter 1.5cm by ultrasound Grade II III LEE mg/day + letrozole 2.5 mg/day (n=40) LEE mg/day + letrozole 2.5 mg/day (n=40) Letrozole 2.5 mg/day (n=40) Primary endpoint Proliferation (Ki67) Secondary endpoints Safety ECG Changes in biomarkers (e.g. phospho-rb and CDK1) PK 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%) A pesar de todo al ser un estudio farmacodinámico, se esperan resultados interesantes.

23 NA-PHER2: PALBO + FUL + PERTU + TRASTU EFECTO KI67 antes, durante y despues de QT neo

24 FELINE: Letrozole plus ribociclib or placebo as neoadjuvant 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) iclib+neoadjuvant&rank=1

25 Inhibidores de Ciclinas en Adyuvancia

26 PALLAS

27 Enfermedad residual tras QT neo PENELOPE B (ANZ 1402 / GBG-78 / BIG 1-13 / NSABP-B-54-I) Phase III study evaluating palbociclib (PD ), 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 Ribociclib not yet open Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2- High Risk EarlyBreast Cancer (EarLEE-1) ociclib+breast&rank=1 Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2- Intermediate Risk Early Breast Cancer (EarLEE-2) (EarLEE-2) ociclib+breast&rank=2

29 Inhibidores de Ciclinas más en 1ª línea

30 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 Stage I N 1 = 15 Stage II N 2 = 31 N 1 =3+12 ER-HER2+ MBC patients 3-4L A Palbociclib +Trastuzumab Palbociclib +Trastuzumab ER+HER2+ MBC patients 3-4L R A M D O M I Z A T I O N 1:1 B1 B2 Safety Run-in phase N r =12 N 1 = 3+12 Palbociclib +Trastuzumab Palbociclib +Trastuzumab + Letrozole N 1 = 6+9 INTERIM ANALISYS Stage I Go on if > 5/15 PFS6 Palbociclib +Trastuzumab Palbociclib +Trastuzumab + Letrozole FINAL ANALISYS Stage I+II Efficacy if > 18/46 PFS6

31 FLIPPER: FUL + PLACEBO vs FUL+ PALBO 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/ ) 1º línea CMM ER+ HER2- Tratadas 5 años y libres de enfermedad 1 año tras finalización de HT adyuvante Metastasicas de novo

32 PARSIFAL: FUL+ PALBO vs PALBO + LET 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 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 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 Estimated primary completion date February 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. (NCT ).

34 MONARCH-3 (Phase 3, 1st-Line) Study Design Phase 3 Study Planned N = 450 (Not yet recruiting) Postmenopausal HR +, HER2 ABC ECOG PS 1 R 2:1 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 No prior systemic therapy for ABC Estimated primary completion date June 2017 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. (NCT ).

35 Randomization 1:1 MONALEESA-7 (Phase 3, 1 st -line): Ribociclib (LEE011) in Premenopausal Women Phase 3 Trial Planned N = 660 (estimated primary completion date: February 2018) Premenopausal women HR +, HER2 ABC No prior hormonal therapy for ABC a Measurable disease or 1 lytic bone lesion ECOG PS 0/1 Tamoxifen / NSAI + Goserelin + Ribociclib (LEE011) b Tamoxifen / NSAI + Goserelin + Placebo b Stratification Factors Presence of liver and/or lung metastases Prior chemotherapy for advanced disease Endocrine therapy partner (tamoxifen vs NSAI) Primary endpoint PFS by local assessment (RECIST v1.1) Key secondary OS Secondary endpoints ORR, CBR, TTR, DoR, ECOG PS, QoL, Safety 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. (NCT )

36 PATINA Mantenimiento antiher2 + HT +/- Palbo tras 1º linea CMM HER2+ A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 therapy + Endocrine therapy vs. Anti- HER2 therapy + Endocrine therapy after induction treatment for Hormone Receptor Positive (HR+)/HER2-Positive MBC

37 Inhibidores de Ciclinas en 2ª línea y sucesivas

38 PALBO + EXE vs CAPECITABINA PEARL (Phase 3, 2nd-Line) (NCT ) Study Design Planned N = 348 Postmenopausal HR +, HER2 MBC refractory to prior NSAI a No prior treatment for advanced disease Measurable disease or lytic bone lesions R 1:1 Palbociclib (125 mg PO daily) + Exemestane (25 mg) Capecitabine (1250 mg/m 2 ) Primary: PFS Endpoints Secondary: ORR, CBR, RD, OS, Safety, biomarkers (cell cycle), HRQoL 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. Stratification Visceral vs nonvisceral metastases Prior sensitivity to hormonal treatment: yes vs no Prior chemotherapy for MBC: yes vs no Country 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; (NCT ). Trial start date: Mar 2014 Estimated primary completion date (primary data): Jan 2018 Trial status: Currently recruiting

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.

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