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

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

EVOLUCIÓN DEL TRATAMIENTO DEL MELANOMA DACARBAZINA Combinaciones de quimioterapia (CVD, Dartmouth) IL 2 ALTAS DOSIS 1975 1980s 1998 IPILIMUMAB VEMURAFENIB 2011 DABRAFENIB ENCORAFENIB BINIMETINIB TRAMETINIB COBIMETINIB 2017 NIVOLUMAB PEMBROLIZUMAB NIVOLUMAB- IPILIMUMAB

HALLMARKS OF CANCER Hanahan D, Weingerg RA. Cell 2000 Jan 7;100(1):57-70. Hanahan D, Weinberg RA. Cell 2011. Vol144 (5): 646-674.

VIA DE LAS MAP KINASAS Dermatol Ther 2015 Sep 5

Salama A K, and Flaherty K T Clin Cancer Res 2013;19:4326-4334

N Engl J Med 2014 N Engl J Med 2015

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

Robert C. ESMO 2016.

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

Robert C. ESMO 2016.

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.

Patients Patients COMBI-v: Duration of Response Dabrafenib + Trametinib Vemurafenib 0 10 20 30 40 Survival, months Complete response Partial response Complete response Partial response 0 10 20 30 40 Survival, months Median DOR (95% CI), months Dabrafenib + Trametinib Vemurafenib All responders (CR + PR) 13.8 (11.3-17.7) 7.9 (7.4-9.3) Complete responders 39.6 (26.5-NR) 29.9 (16.7-NR) Partial responders 10.8 (9.2-12.0) 7.3 (5.8-7.5) 15 36 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.

Robert C. ESMO 2016

Flaherty K. ASCO 2016

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.

IMPACTO DE LOS FACTORES PRONÓSTICOS

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.

OS Probability PFS Probability COMBI-v: Elevated LDH (> ULN) OS PFS 1.00 Dabrafenib + trametinib (n = 119) Median OS, 10.8 (95% CI, 8.9-14.4) 1.00 Dabrafenib + trametinib (n = 119) Median PFS, 5.5 (95% CI, 5.3-7.3) 0.75 0.75 Vemurafenib (n = 114) Median PFS, 4.0 (95% CI, 3.7-5.4) HR, 0.70 (95% CI, 0.53-0.93) 0.50 0.50 0.25 0.00 Patients at risk, n D + T 119 Vem 114 Vemurafenib (n = 114) Median OS, 8.7 (95% CI, 7.3-10.7) HR, 0.79 (95% CI, 0.59-1.07) 2-y OS, 27% 2-y OS, 25% Months From Randomization 3-y OS, 20% 3-y OS, 14% 0 6 12 18 24 30 36 42 90 77 52 37 38 31 27 23 20 16 15 10 3 3 0.25 0.00 Patients at risk, n D + T 119 Vem 114 2-y PFS, 13% 2-y PFS, 4% 0 6 12 18 24 30 36 49 32 Months From Randomization 26 12 15 7 13 3 12 3 3-y PFS, 6% 3-y PFS, 3% 4 2 23 Robert C. ESMO 2016.

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, 14.9-21.2) 0.75 0.50 0.25 0.00 Patients at risk, n D + T 233 Vem 238 Vemurafenib (n = 238) Median OS, 21.6 (95% CI, 18.2-26.4) HR, 0.61 (95% CI, 0.47-0.79) 2-y OS, 66% 2-y OS, 46% Months From Randomization 3-y OS, 56% 3-y OS, 39% 0 6 12 18 24 30 36 42 221 212 193 166 163 123 144 96 130 87 112 71 30 19 0.75 0.50 0.25 0.00 Vemurafenib (n = 238) Median PFS, 9.2 (95% CI, 7.6-10.9) HR, 0.56 (95% CI, 0.44-0.70) Patients at risk, n D + T Vem 233 238 187 130 2-y PFS, 39% 2-y PFS, 21% Months From Randomization 3-y PFS, 33% 3-y PFS, 13% 0 6 12 18 24 30 36 42 136 70 105 48 80 24 68 13 59 9 25 2 24 NR, not reached. Robert C. ESMO 2016.

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, 18.1-29.7) 0.75 2-y OS, 79% 3-y OS, 70% 0.75 0.50 2-y OS, 52% 3-y OS, 46% 0.50 2-y PFS, 46% 3-y PFS, 39% 0.25 0.00 Vemurafenib (n = 161) Median OS, 26.4 (95% CI, 21.5-46.8) HR, 0.47 (95% CI, 0.33-0.67) 0.25 0.00 Vemurafenib (n = 161) Median PFS, 10.7 (95% CI, 9.0-11.1) HR, 0.52 (95% CI, 0.39-0.70) 2-y PFS, 27% 3-y PFS, 16% Patients at risk, n D + T 141 Vem 161 0 6 12 18 24 30 36 42 135 146 Months From Randomization 125 125 115 91 104 75 96 68 83 58 21 16 Patients at risk, n D + T 141 Vem 161 0 6 12 18 24 30 36 42 123 93 98 50 Months From Randomization 76 40 59 22 49 12 43 8 19 2 26 Robert C. ESMO 2016.

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 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Overall Survival (OS) Median (95% CI), mo Phase 1/2 D + T 25.0 (17.5 36.5) COMBI-d D + T 25.1 (19.2 NR) COMBI-d D + P 18.7 (15.2 23.7) COMBI-v D + T 25.6 (22.6 NR) COMBI-v V 18.0 (15.6 20.7) 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Months Long G, et al. Lancet Oncol Dec 2016 2 7

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 352 215 155 COMBI-d 211 139 99 Phase 1/2 54 42 36 TOTAL 617 396 290 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 2015 2 8

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

OS Probability 0.0 0.2 0.4 0.6 0.8 1.0 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 < 3 237 Normal LDH, Disease Sites 3 161 206 119 103 58 14 5 LDH > 1 x ULN, ECOG = 0 LDH > 1 x ULN, ECOG 1 LDH > 2 x ULN 93 56 70 61 23 22 15 9 1 0 1 0 a Factors identified by the regression tree analysis. 0 12 24 36 Months 30 PRESENTED BY GV LONG AT SMR 2015

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

PFS Probability 0.0 0.2 0.4 0.6 0.8 1.0 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. 0 12 24 36 Months 237 149 53 8 161 69 23 2 149 40 9 0 70 4 0 0 PRESENTED BY GV LONG AT SMR 2015 3 2

ENSAYOS POR VENIR

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) NCT02224781 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

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.