Evolución de la supervivencia en melanoma metastásico BRAF mutado. Nuevas estrategias de tratamiento.

Transcripción

1 Evolución de la supervivencia en melanoma metastásico BRAF mutado. Nuevas estrategias de tratamiento. Dra. Ainara Soria Rivas Servicio de Oncología Médica Hospital Ramón y Cajal

2 Cuál es la supervivencia del melanoma? CA Cancer J Clin. 2004; 54(3):131-49

3 Evolución en el tratamiento del melanoma DACARBAZINA Combinaciones de quimioterapia (CVD, Dartmouth) IL 2 ALTAS DOSIS s

4 Cuál es la eficacia de los tratamientos clásicos? N Engl J Med 2011 Jun 2;364(22):

5 NCCN Guidelines V Melanoma SYSTEMIC THERAPY OPTIONS FOR ADVANCED OR METASTATIC MELANOMA Clinical trial (preferred) Dacarbazine Temozolamide High dose IL-2 Dacarbazine or Temozolamide-based combination chemotherapy/biochemotherapy (category 2B) Paclitaxel (category 2B) Paclitaxel/Cisplatin (category 2B) Paclitaxel/Carboplatin (category 2B)

6 Evolución en el tratamiento del melanoma DACARBAZINA Combinaciones de quimioterapia (CVD, Dartmouth) IL 2 ALTAS DOSIS s 1998 IPILIMUMAB VEMURAFENIB 2011 DABRAFENIB TRAMETINIB COBIMETINIB NIVOLUMAB PEMBROLIZUMAB

7 HALLMARKS OF CANCER Mutación V600E B RAF Aprox. 50% melanomas VEMURAFENIB, DABRAFENIB Hanahan D, Weingerg RA. Cell 2000 Jan 7;100(1): Hanahan D, Weinberg RA. Cell Vol144 (5):

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9 TRAMETINIB COBIMETINIB Salama A K, and Flaherty K T Clin Cancer Res 2013;19: by American Association for Cancer Research

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11 Unresectable stage IIIC IV Melanoma BRAF V600E/K No prior sistemic therapy (N 423) 1:1 Dabrafenib 150 mg BID Trametinib 2 mg QD Dabrafenib 150 mg BID Placebo QD Disease progression, Unacceptable toxicity, or Withdrawal of consent Objetivo principal: PFS investigator assessed Objetivos secundarios: OS, ORR, Seguridad, farmacocinética. Long GV, et al. N Engl J Med Sep 2014

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13 COMBI-V: Características basales Dabrafenib Trametinib (n = 352) Vemurafenib (n = 352) Total (N = 704) Median age (range), years 55 (18-91) 54 (18-88) 55 (18-91) Male sex, n (%) 208 (59) 180 (51) 388 (55) ECOG PS, n (%) 0/1 248 (71)/102 (29) 248 (70)/104 (30) 496 (71)/206 (29) BRAF V600 mutation status, n (%) a V600E mutation positive V600K mutation positive Metastasis stage at screening, n (%) M0 M1a M1b M1c 312 (90) 34 (10) 14 (4) 55 (16) 61 (17) 221 (63) 317 (90) 34 (10) 26 (7) 50 (14) 67 (19) 208 (59) 629 (89) 68 (10) 40 (6) 105 (15) 128 (18) 429 (61) Baseline LDH, n (%) > ULN/ ULN 118 (34)/233 (66) 114 (32)/238 (68) 232 (33)/471 (67) Visceral disease at baseline, n (%) b Yes/ No 278 (79)/73 (21) 271 (77)/81 (23) 549 (78)/154 (22) Number of disease sites at baseline, n (%) c < 3/ (50)/174 (50) 201 (57)/151 (43) 378 (54)/325 (46)

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15 COMBI-v: Investigator-Assessed Progression- Free Survival Proportion Alive and Progression Free Vemurafenib Median PFS, 7.3 mo (95% CI, mo) HR, 0.61 (95% CI, ); P < Dabrafenib Trametinib Median PFS, 12.6 mo (95% CI, mo) Time From Randomization, months Patients at risk a Trametinib Vemurafenib a Data cutoff: 15 March 2015.

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17 COMBI-V: Best confirmed Response Best Confirmed Response Dabrafenib Trametinib (n = 351) Vemurafenib (n = 350) Complete response, n (%) 59 (17) 36 (10) Partial response, n (%) 172 (49) 150 (43) Stable disease, n (%) 87 (25) 102 (29) Progressive disease, n (%) 22 (6) 39 (11) Not evaluable, n (%) 12 (3) 25 (7) Response rate, n (%) [95% CI] 231 (66) [ ] 186 (53) [ ] Difference in ORR, % [95% CI] 13 [ ] P value DOR (95% CI), months 13.8 ( ) 8.5 ( )

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20 Objetivo principal: PFS investigator assessed Objetivos secundarios: OS, ORR, Seguridad, PFS IRC assessed Larkin J, et al. N Engl J Med, Sep 2014

21 cobrim Patient Characteristics Cobimetinib Vemurafenib n = 247 Placebo Vemurafenib n = 248 Median age (range), years 56 (23 88) 55 (25 85) Sex, n (%) Geographic region, n (%) ECOG, n (%) Male Female Australia/New Zealand/Other Europe North America PS 0 PS 1 PS (59) 101 (41) 40 (16) 182 (74) 25 (10) 184 (76) 58 (24) 1 (<1) 140 (57) 108 (44) 38 (15) 184 (74) 26 (11) 164 (67) 80 (33) 0 Previously treated brain metastasis, n (%) 1 (<1) 2 (0.8) Stage at randomization, n (%) Unresectable stage IIIc Stage IV, M1a Stage IV, M1b Stage IV, M1c 21 (9) 40 (16) 40 (16) 146 (59) 13 (5) 40 (16) 42 (17) 153 (62) Elevated LDH, n (%) 112 (46) 104 (43) Median follow up a (range), months 14.2 ( ) LDH, lactate dehydrogenase. a The data cutoff was January 16, The median follow up in the primary analysis was 7.3 months (range, ). Larkin J et al. N Engl J Med. 2014;371:

22 cobrim Updated Investigator-Assessed PFS Kaplan Meier Plot for PFS Intent to Treat Population 100 ITT Population Cobi Vem n = 247 Pbo Vem n = 248 PFS events, n (%) 143 (57.9) 180 (72.6) Survival Distribution Function (%) Cobimetinib vemurafenib (n=247) Placebo vemurafenib (n=248) Censored Median PFS, months (95% CI) HR a (95% CI) b ( ) 0.58 b ( ) 7.20 b ( ) Data cutoff of January 16, 2015 was 1 year from enrollment of last patient No. of patients at risk Vemurafenib cobimetinib Vemurafenib placebo 1 Months 5 Months 9 Months 13 Months 17 Months 21 Months 25 Months Time a Stratified HR. b The median PFS was 6.2 months in Pbo Vem, and 9.9 months in Cobi Vem (HR, 0.51; 95% CI, ) at the May 9, 2014 data cutoff. Larkin J et al. N Engl J Med. 2014;371:

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24 cobrim Updated Best Objective Response Rate and Duration of Response Cobimetinib Vemurafenib n = 247 Placebo Vemurafenib n = 248 Complete response (CR), n (%) 39 (15.8) 26 (10.5) Partial response, n (%) 133 (53.8) 98 (39.5) Objective response rate (ORR), n (%) 172 (69.6) (95% CI, ) 124 (50.0) (95% CI, ) Difference in ORR, % a (95% CI, ) Duration of response Patients with event, n (%) Median (95% CI) Range 84 (48.8) ( ) (58.9) 9.23 ( ) a At the primary analysis ORR was 68% and 45%, respectively, and CR was 10% and 4%, respectively. Larkin J et al. N Engl J Med. 2014;371: Data cutoff was January 16,

25 Larkin J, et al. N Engl J Med, Sep 2014

26 En conclusión La combinación de Inhibidor de BRAF inhibidor de MEK frente a inhibidor de BRAF: Mejora lasupervivencia libre de progresión ( meses). Aumenta la supervivencia global (aprox 25 meses). Aumenta la tasa de respuestas ( 69% ORR). Mejora la tolerancia del tratamiento (reduce toxicidad cutánea).

27 MUCHAS GRACIAS