Melanoma metastásico: Tratamiento de primera línea en BRAF mutado. Dra Elena Gallardo Martín

Transcripción

1 Melanoma metastásico: Tratamiento de primera línea en BRAF mutado Dra Elena Gallardo Martín

2 Después de ASCO qué hago?

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4 Espero la verdadera respuesta?? Pero, es esta la verdadera pregunta??

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7 Mutational Profile of Melanoma

8 Ensayos fases III de 1ª (2º línea) en MM que incluyen BRAF mutados y que se aproximan a mis dudas actuales: -COBRIM -COMBI-d -COMBI-v -KEYNOTE-006 -CHECKMATE-067

9 TERAPIA DIRIGIDA

10 Terapia dirigida Factor pronóstico fundamental LDH. 3 Estudios fases III de combinación: Combi-d (423p) y cobrim (495p): PFS Combi-v ( 704 p): OS

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19 CASO 1

20 ELIPSE DE PIEL Y TEJIDO CELULAR SUBCUTÁNEO PROCEDENTE DE REGIÓN TORÁCICA IZQUIERDA, CON: - MELANOMA NODULAR DE 4,5X3,5X1,7 CM DE DIÁMETRO. - ÍNDICE DE BRESLOW: 17 MM. - ULCERACIÓN HISTOLÓGICA. - NIVEL DE CLARK: V. - ÍNDICE MITÓTICO POR MILIMETRO CUADRADO: 4. - SATELITOSIS. - DISTANCIA A AMBOS ÁNGULOS: 1 CM. - DISTANCIA A BORDES LATERALES: 5 MM. - NO INVASIÓN NEURAL Ó ANGIOLINFÁTICA. - AUSENCIA DE LINFOCITOS INFILTRANDO EL TUMOR (TIL). (ESTADIO TNM: pt4b)

21 CASO 2

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23 Four Baseline Factors Influenced PFSa Presented By Keith Flaherty at 2016 ASCO Annual Meeting

24 PFS by LDH and Number of Disease Sitesa Presented By Keith Flaherty at 2016 ASCO Annual Meeting

25 Five Baseline Factors Influenced OSa Presented By Keith Flaherty at 2016 ASCO Annual Meeting

26 OS by LDH, Number of Disease Sites, and ECOGa Presented By Keith Flaherty at 2016 ASCO Annual Meeting

27 INMUNOTERAPIA

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29 Inmunoterapia en general Pembrolizumab es superior a Ipilimumab en PFS y OS. Nivolumab es superior a Ipilimumab en PFS y ORR. Nivolumab+Ipilimumab es superior en PFS y ORR a Ipilimumab, con incremento de la toxicidad.

30 KEYNOTE-006 Study Design Presented By Jacob Schachter at 2016 ASCO Annual Meeting

31 Baseline Characteristics Presented By Jacob Schachter at 2016 ASCO Annual Meeting

32 Progression-Free <br />Survivala Presented By Jacob Schachter at 2016 ASCO Annual Meeting

33 Overall Survival in Key Subgroups Presented By Jacob Schachter at 2016 ASCO Annual Meeting

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35 9505 Updated Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatmentnaïve Patients With Advanced Melanoma (Checkmate 067) Jedd D. Wolchok* ASCO

36 CA : Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone Stratify by: Unresectable or Metatastic Melanoma Previously untreated 945 patients Tumor PDL1 expression Random ize 1:1:1 a BRAF mutation status N= 314 N= 316 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W NIVO 3 mg/kg Q2W + IPI-matched placebo AJCC M stage N= 315 Treat until progressi onb or unaccepta ble toxicity IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses b Patients could have been treated beyond progression under protocol-defined circumstances a ASCO

37 Study Endpoints: NIVO+IPI or NIVO vs IPI Co-primary endpoints: Progression-free survival (PFS) and overall survival (OS) [intentto-treat population] Secondary and exploratory endpoints: Objective response rate (ORR) by RECIST v1.1 Efficacy by tumor PD-L1 expression level Safety profile (in patients who received 1 dose of study drug) Current analysis: Efficacy and safety update with follow-up of at least 18 months (database lock: Nov 2015) Median follow-up at time of database lock was 20.7 months OS remains immature ASCO

38 Progression-Free Survival (Intent-toTreat Population) 100 NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) Progression-free PercentageSurvival of PFS (%) Median PFS, months (95% CI) 11.5 (8.9, 16.7) 6.9 (4.3, 9.5) 2.9 (2.8, 3.4) HR (99.5% CI) vs. IPI 0.42 (0.31, 0.57)a 0.55 (0.43, 0.76)a -- HR (95% CI) vs. NIVO a 0.76 (0.60, Stratified log-rank P< vs. 0.92)b 49 % % NIVO+IPI NIVO IPI Number of patients at risk: Nivolumab + Ipilimumab 314 Nivolumab 316 Ipilimumab % PFS per Investigator (months) Exploratory endpoint b 39 % 18 % 3 IPI 46 % Database lock Nov 2015 ASCO

39 Response to Treatment NIVO + IPI (N = 314) 57.6 (52.0, 63.2) <0.001 NIVO (N = 316) 43.7 (38.1, 49.3) <0.001 IPI (N = 315) 19.0 (14.9, 23.8) -- Complete response Partial response Stable disease Progressive disease Unknown NR (20.5, NR) 22.3 (20.7, NR) 14.4 (8.3, NR) ORR, % (95% CI)a Two-sided P value vs IPI Best overall response, % Median duration of response, months (95% CI) Ongoing response among responders, % By RECIST v1.1 a NR = not reached Database lock Nov 2015 ASCO

40 PFS in Patient Subgroups (18 month follow-up) Total population Median PFS Events/patien (95% CI) ts 11.5 (8.9, 22.2) 161/ (4.3, 9.5) Hazard ratio (95% CI) 0.42 (0.34, 0.52) 183/ (0.45, 0.67) 11.3 (8.3, 22.2) 110/ (4.9, 14.3) 120/ (8.0, NR) 51/ (2.8, 9.3) 63/ (0.33, 0.53) 0.48 (0.38, 0.60) 0.44 (0.31, 0.63) 0.76 (0.54, 1.07) 8.5 (5.5, 13.2) 5.3 (2.8, 7.1) 108/ / (0.38, 0.63) 0.60 (0.47, 0.76) NR (11.5, NR) 9.7 (6.9, 22.0) 4.2 (2.8, 9.3) 2.8 (2.6, 4.0) 87/ /196 74/114 76/ (0.28, 0.48) 0.52 (0.41, 0.67) 0.47 (0.34, 0.64) 0.59 (0.43, 0.80) 2.8 (2.2, 4.4) 29/ (0.23, 0.73) 2.6 (1.7, 2.8) 30/ (0.36, 1.09) BRAF Wild-type Mutant M Stage M1c Baseline LDH ULN >ULN >2x ULN ASCO 2016 Age, years 65 and 11.1 (8.3, NR) < (6.7, 24.9) IPI better NIVO or NIVO+IPI better 51/94 41/79 NIVO+IPI 0.39 (0.27, 0.56) 0.37 (0.25, 0.54) NIVO 43

41 ORR in Patient Subgroups (18 month follow-up) Total population Unweighted ORR difference vs IPI ORR (Patients) 57.6% (314) 38.6 (31.3, 45.2) 43.7% (316) 24.6 (17.5, 31.4) 53.3% (212) 46.8% (218) 66.7% (102) 36.7% (98) 35.6 (26.8, 43.6) 29.1 (20.5, 37.1) 44.7 (31.5, 55.6) 14.7 (2.0, 26.8) 51.4% (185) 38.6% (184) 36.5 (27.3, 44.9) 23.8 (14.9, 32.2) 65.3% (199) 51.5% (196) 44.7% (114) 30.4% (112) 40.6 (31.1, 48.9) 26.8 (17.3, 35.6) 35.2 (24.1, 45.2) 20.8 (10.5, 30.7) 37.8% (37) 37.8 (20.0, 53.9) 21.6% (37) 21.6 (6.3, 37.2) BRAF Wild-type Mutant M Stage M1c Baseline LDH ULN >ULN >2x ULN 70 ASCO 2016 Age, years 65 and < % (94) 48.1% (79) IPI better NIVO or NIVO+IPI better 39.5 (25.8, 51.0) 30.1 (16.0, 42.8) NIVO+IPI NIVO 44

42 Progression-free Survival by Tumor PDL1 Expression Percentage of PFS Median PFS, months (95% CI) 11.1 (8.0, 22.2) HR (95% CI) vs NIVO 0.74 endpoint (0.58,*Exploratory 0.96)a NIVO + IPI NIVO IPI Number of patients at risk: NIVO + IPI 210 NIVO 208 IPI PFS (months) NIVO (N = 80) IPI (N = 75) NR (9.7, NR) (8.9, NR) (2.8, 4.2) HR (95% CI) vs. NIVO endpoint (0.54,aExploratory 1.41)a NIVO + IPI NIVO IPI 0 6 IPI (N = 68) Median PFS, months (95% CI) 10 3 Tumor PD-L1 Expression Level 5% NIVO (2.8, 7.1) (2.8, 3.1) IPI (N = NIVO IPI 210) (N = 208) (N = 202) Percentage of PFS 100 Tumor PD-L1 Expression Level <5% NIVO + 0 Number of patients at risk: 0 NIVO + IPI 68 0 NIVO 80 0 IPI PFS (months) For the original PD-L1 PFS analysis, the descriptive hazard ratio comparing NIVO+IPI vs NIVO was 0.96, with a similar Database lockmedian Nov 2015 PFS in both groups (14 months) ASCO

43 Response to Treatment by Tumor PD-L1 Expressiona PD-L1 ( 5%) PD-L1 (<5%) NIVO+IPI NIVO IPI ORR, % (95% CI) 72.1 (59.9, 82.3) 57.5 (45.9, 68.5) 21.3 (12.7, 32.3) Median duration of response, months NR 20.7 NR ORR, % (95% CI) 54.8 (47.8, 61.6) 41.3 (34.6, 48.4) 17.8 (12.8, 23.8) Median duration of response, months NR Pre-treatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated BMS/Dako assay) Database lock Nov 2015 a ASCO

44 Safety Summary Updated safety information with 9 additional months of follow-up were consistent with the initial report NIVO+IPI (N = 313) NIVO (N = 313) IPI (N = 311) Patients reporting event, % Any grade Grade 3-4 Any grade Grade 3-4 Any grade Grade 3-4 Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation Treatment-related deatha % of patients who discontinued NIVO+IPI due to treatment-related AEs achieved a response One reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation) Database lock Nov 2015 a ASCO

45 Selección de casos/selección de tratamiento Metástasis cerebrales activas Alta carga de enfermedad/ Número de órganos afectados LDH Interesa rapidez de respuesta? Qué toxicidad vamos a asumir? Factores predictivos de respuesta

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