Tratamiento de combinación en el melanoma irresecable o avanzado BRAF + Dra. Ainara Soria Rivas Servicio de Oncología Médica

Transcripción

1 Tratamiento de combinación en el melanoma irresecable o avanzado BRAF + Dra. Ainara Soria Rivas Servicio de Oncología Médica

2 EVOLUCIÓN DEL TRATAMIENTO DEL MELANOMA DACARBAZINA Combinaciones de quimioterapia (CVD, Dartmouth) IL 2 ALTAS DOSIS s 1998 IPILIMUMAB VEMURAFENIB 2011 DABRAFENIB ENCORAFENIB BINIMETINIB TRAMETINIB COBIMETINIB 2017 NIVOLUMAB PEMBROLIZUMAB NIVOLUMAB- IPILIMUMAB

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4 HALLMARKS OF CANCER Hanahan D, Weingerg RA. Cell 2000 Jan 7;100(1): Hanahan D, Weinberg RA. Cell Vol144 (5):

5 VIA DE LAS MAP KINASAS Dermatol Ther 2015 Sep 5

6 Salama A K, and Flaherty K T Clin Cancer Res 2013;19:

7 N Engl J Med 2014 N Engl J Med 2015

8 COMBI-D: Supervivencia libre de progresión Flaherty K. ASCO 2016

9 Robert C. ESMO 2016.

10 COMBI-D: Supervivencia global 58% de los pacientes vivos, se encuentran en tratamiento con D +T Flaherty K. ASCO 2016

11 Robert C. ESMO 2016.

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13 COMBI-v: Best Response Best Confirmed Response Overall response rate, n (%) [95% CI] Dabrafenib + Trametinib (n = 352) 236 (67) [62-72] Vemurafenib (n = 352) a 187 (53) [48-58] Complete response (CR), n (%) 68 (19) 41 (12) Partial response (PR), n (%) 168 (48) 146 (41) Stable disease (SD), n (%) 83 (24) 109 (31) Progressive disease, n (%) 22 (6) 37 (11) Not evaluable, n (%) 11 (3) 18 (5) 14 Robert C. ESMO 2016.

14 Patients Patients COMBI-v: Duration of Response Dabrafenib + Trametinib Vemurafenib Survival, months Complete response Partial response Complete response Partial response Survival, months Median DOR (95% CI), months Dabrafenib + Trametinib Vemurafenib All responders (CR + PR) 13.8 ( ) 7.9 ( ) Complete responders 39.6 (26.5-NR) 29.9 (16.7-NR) Partial responders 10.8 ( ) 7.3 ( ) of 68 patients (53%) with a CR on dabrafenib + trametinib are still in CR 21 of 41 patients (51%) with a CR on vemurafenib are still in CR Robert C. ESMO 2016.

15 Robert C. ESMO 2016

16 Flaherty K. ASCO 2016

17 COMBI-v: Post-Progression Systemic Therapy Post-Progression Systemic Therapy Dabrafenib + Trametinib (n = 187) Vemurafenib (n = 248) Subsequent anticancer therapy, n (%) Immunotherapy 108 (58) 123 (50) Ipilimumab 88 (47) 100 (40) Nivolumab 3 (2) 3 (1) Pembrolizumab 14 (7) 13 (5) Radiotherapy 102 (55) 120 (48) Small-molecule targeted therapy 59 (32) 115 (46) a Chemotherapy 43 (23) 71 (29) Biologic therapy 14 (7) 12 (5) Hormonal therapy 0 2 (< 1) Median time from study treatment discontinuation to start of subsequent systemic therapy 12 days 11 days A total of 187 patients (53%) in the dabrafenib + trametinib arm and 248 patients (70%) in the vemurafenib arm received post-study anticancer therapy 18 a Includes patients who crossed over from vemurafenib to dabrafenib + trametinib. Robert C. ESMO 2016.

18 IMPACTO DE LOS FACTORES PRONÓSTICOS

19 COMBI-v: Complete Responders Baseline Characteristics Dabrafenib + Trametinib (n = 68) Vemurafenib (n = 41) Median age (range), years 59 (26-80) 50 (23-79) Male sex, n (%) 35 (51) 15 (37) ECOG PS, n (%) 0/1 62 (91)/5 (7) a 32 (78)/9 (22) BRAF V600 mutation status, n (%) V600E mutation positive V600K mutation positive 64 (94) 4 (6) 40 (98) 1 (2) Metastasis stage at screening, n (%) b M0 M1a M1b M1c 6 (9) 18 (27) 17 (25) 26 (39) 2 (5) 15 (37) 5 (12) 18 (44) Baseline LDH, n (%) ULN/> ULN 64 (94)/4 (6) 36 (88)/5 (12) Visceral disease at baseline, n (%) Yes/No 44 (66)/23 (34) 24 (59)/17 (41) Number of organ sites with metastasis, n (%) < 3/ 3 57 (84)/11 (16) 37 (90)/4 (10) 20 a One patient had missing ECOG PS at baseline; b One patient in the Vem arm had a metastasis stage of MX at screening.

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22 OS Probability PFS Probability COMBI-v: Elevated LDH (> ULN) OS PFS 1.00 Dabrafenib + trametinib (n = 119) Median OS, 10.8 (95% CI, ) 1.00 Dabrafenib + trametinib (n = 119) Median PFS, 5.5 (95% CI, ) Vemurafenib (n = 114) Median PFS, 4.0 (95% CI, ) HR, 0.70 (95% CI, ) Patients at risk, n D + T 119 Vem 114 Vemurafenib (n = 114) Median OS, 8.7 (95% CI, ) HR, 0.79 (95% CI, ) 2-y OS, 27% 2-y OS, 25% Months From Randomization 3-y OS, 20% 3-y OS, 14% Patients at risk, n D + T 119 Vem y PFS, 13% 2-y PFS, 4% Months From Randomization y PFS, 6% 3-y PFS, 3% Robert C. ESMO 2016.

23 OS Probability PFS Probability COMBI-v: Normal LDH ( ULN) OS PFS 1.00 Dabrafenib + trametinib (n = 233) Median OS, NR (95% CI, 35.1-NR) 1.00 Dabrafenib + trametinib (n = 233) Median PFS, 17.5 (95% CI, ) Patients at risk, n D + T 233 Vem 238 Vemurafenib (n = 238) Median OS, 21.6 (95% CI, ) HR, 0.61 (95% CI, ) 2-y OS, 66% 2-y OS, 46% Months From Randomization 3-y OS, 56% 3-y OS, 39% Vemurafenib (n = 238) Median PFS, 9.2 (95% CI, ) HR, 0.56 (95% CI, ) Patients at risk, n D + T Vem y PFS, 39% 2-y PFS, 21% Months From Randomization 3-y PFS, 33% 3-y PFS, 13% NR, not reached. Robert C. ESMO 2016.

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25 OS Probability PFS Probability COMBI-v: Normal LDH and < 3 Organ Sites With Metastasis OS PFS 1.00 Dabrafenib + trametinib (n = 141) Median OS, NR (95% CI, NR-NR) 1.00 Dabrafenib + trametinib (n = 141) Median PFS, 23.0 (95% CI, ) y OS, 79% 3-y OS, 70% y OS, 52% 3-y OS, 46% y PFS, 46% 3-y PFS, 39% Vemurafenib (n = 161) Median OS, 26.4 (95% CI, ) HR, 0.47 (95% CI, ) Vemurafenib (n = 161) Median PFS, 10.7 (95% CI, ) HR, 0.52 (95% CI, ) 2-y PFS, 27% 3-y PFS, 16% Patients at risk, n D + T 141 Vem Months From Randomization Patients at risk, n D + T 141 Vem Months From Randomization Robert C. ESMO 2016.

26 OS Probability POOLED ANALYSIS DABRAFENIB-TRAMETINIB Phase 1/2: dabrafenib + trametinib 1 COMBI-d: dabrafenib + trametinib vs dabrafenib 2 COMBI-v: dabrafenib + trametinib vs vemurafenib 3 Pooled Analysis Overall Survival (OS) Median (95% CI), mo Phase 1/2 D + T 25.0 ( ) COMBI-d D + T 25.1 (19.2 NR) COMBI-d D + P 18.7 ( ) COMBI-v D + T 25.6 (22.6 NR) COMBI-v V 18.0 ( ) Months Long G, et al. Lancet Oncol Dec

27 Methods: Patients Treatment-naive patients randomized to dabrafenib 150mg BID + trametinib 2mg QD: Randomize PFS OS Events, Study d, n a Events, n n COMBI-v COMBI-d Phase 1/ TOTAL Median duration of follow-up was 20.0 months 221 (36%) patients remained progression-free and alive at analysis a Intention-to-treat population. BID, twice daily; PFS, progression-free survival; QD, once daily. PRESENTED BY GV LONG AT SMR

28 Five Baseline Factors Influenced OS LDH Normal N = 617 LDH ULN Disease Sites < 3 N = 398 1Y = 85% 2Y = 67% 3Y = 57% Disease Sites 3 N = 219 1Y = 54% 2Y = 25% 3Y = 7% LDH >1-2 ULN LDH 2 ULN N = 237 1Y = 90% 2Y = 75% 3Y = 70% N = 161 1Y = 76% 2Y = 55% 3Y = 38% N = 149 1Y = 60% 2Y = 33% 3Y = 9% N = 70 1Y = 40% 2Y = 7% 3Y = 7% ECOG = 0 ECOG 1 a Regression tree analysis. NE, not estimable. N = 93 1Y = 71% 2Y = 43% 3Y = NE N = 56 1Y = 42% 2Y = 19% 3Y = 16% 29 PRESENTED BY GV LONG AT SMR 2015

29 OS Probability OS by LDH, Number of Disease Sites, and ECOG Normal LDH, Disease Sites < 3 Normal LDH, Disease Sites 3 LDH >1-2 x ULN, ECOG = 0 LDH >1-2 x ULN, ECOG 1 LDH > 2 x ULN No. at risk Normal LDH, Disease Sites < Normal LDH, Disease Sites LDH > 1 x ULN, ECOG = 0 LDH > 1 x ULN, ECOG 1 LDH > 2 x ULN a Factors identified by the regression tree analysis Months 30 PRESENTED BY GV LONG AT SMR 2015

30 Four Baseline Factors Influenced PFS N = 617 LDH Normal LDH ULN N = 398 1Y = 61% 2Y = 40% 3Y = 33% N = 219 1Y = 24% 2Y = 13% 3Y = 13% Disease Sites < 3 Disease Sites 3 LDH >1-2 ULN LDH 2 ULN N = 237 1Y = 68% 2Y = 46% 3Y = 42% N = 161 1Y = 50% 2Y = 29% 3Y = 17% N = 149 1Y = 32% 2Y = 18% 3Y = 18% N = 70 1Y = 8% 2Y = 2% 3Y = 2% 31 a Regression tree analysis. PRESENTED BY GV LONG AT SMR 2015

31 PFS Probability PFS by LDH and Number of Disease Sites Normal LDH, Disease Sites < 3 Normal LDH, Disease Sites 3 LDH >1-2 x ULN LDH > 2 x ULN No. at risk Normal LDH, Disease Sites < 3 Normal LDH, Disease Sites 3 LDH > 1 x ULN LDH > 2 x ULN a Factors identified by the regression tree analysis Months PRESENTED BY GV LONG AT SMR

32 ENSAYOS POR VENIR

33 Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma National Cancer Institute (NCI) NCT Arm A IPILIMUMAB + NIVOLUMAB Progresión o toxicidad DABRAFENIB + TRAMETINIB Arm B DABRAFENIB + TRAMETINIB Progresión o toxicidad IPILIMUMAB + NIVOLUMAB Primary Outcome: OS rate, defined as the proportion of patients alive after 2 years of follow-up time. Secondary Outcome: PFS, evaluated based on RECIST version 1.1 Response rate according to RECIST version 1.1 Toxicity rate

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39 CONCLUSIONES Dabrafenib y Trametinib han demostrado: Aumentar la SLP (12,1 meses). Aumentar la supervivencia global (26,1 meses). Alta tasa de respuestas: ORR 69% (16% RC) y 24% EE. Factores de buen pronóstico: LDH normal y menos de 3 localizaciones preciden un beneficio más prolongado del tratamiento y mayor probabilidad de respuesta completa.