Futuro de las combinaciones (de inmunoterapia) en el tratamiento del melanoma avanzado Iván Márquez Rodas MD, PhD Servicio de Oncología Médica Hospital General Universitario Gregorio Marañón
DISCLOSURES Advisory role: Amgen, BMS, GSK, Novartis, MSD, Roche, Pierre Fabre, Bioncotech Honoraria : BMS, GSK, Roche, Celgene, MSD, Amgen, Novartis Clinical trial participation as PI: BMS, GSK, Roche, Novartis, MSD, Amgen, Ab Science, Bioncotech
Por qué combinar? La inmunoterapia es un tratamiento básico en melanoma Anti PD-1 en monoterapia ha demostrado aumento de SLP y SG frente a QT y frente a ipilimumab Sin embargo, al año de tratamiento, en torno a un 30% de los pacientes fallecen, y a los 2 años, en torno a un 45% Existe evidencia preclínica (y clínica) de que combinar varias estrategias es sinérgico en varios sentidos
TRES ESTRATEGIAS PROGRESIÓN SECUENCIA RESCATE COMBINACIÓN SINCRÓNICA
RAZÓN PARA LA COMBINACIÓN SINCRÓNICA: CURVAS DE SUPERVIVENCIA LIBRE DE PROGRESIÓN Schachter ASCO 2016 Atkinson SMR 2015
Chen and Mellman Immunity 2013
Chen and Mellman Immunity 2013
ipilimumab T-VEC DTIC Fotemustina RDT BRAF/MEK inh Pembrolizumab Nivolumab Epacadostat Chen and Mellman Immunity 2013
DTIC Fotemustina RDT BRAF/MEK inh Chen and Mellman Immunity 2013
DTIC 11.2 vs 9.1 m Robert NEJM 2011 Ascierto et al ESMO 2016
Antecedente: fotemustina es igual a DTIC salvo por un mayor tiempo a la aparición de MTS SNC Avril 2004 JCO 13 m OS 29% 12m 12,7 m OS 28% 12m 100% asintomaticos 35% RDT previa Di Giacomo Annals Oncol 2016
RADIOTERAPIA Patel et al 2015 Neurooncology
RADIOTHERAPY AND ABSCOPAL Postow, 2012, NEJM
IPILIMUMAB + WHOLE BRAIN RDT IN PATIENTS WITH MELANOMA AND BRAIN METASTASES (GRAY-B) PFS 3m OS 4,5m 29% 12m Lopez Martin et al ESMO 2016
POST CXA Y NO CXA NIVOLUMAB NR 12m Ahmed et al 2016 Ann Oncol
INHIBIDORES DE BRAF: RÁPIDOS, POTENTES INHIBIDORES DE CTLA-4: LENTOS, PERSISTENTES DC comics
Ribas NEJM 2013
2/7 pacientes experimentaron colitis grave con perforación Estudio cerrado para el triplete con la combinación Minor 2015 Pigment Cell Mel Res
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NUEVAS COMBINACIONES La combinación de inh BRAF e inh de MEK producen respuesta inmuno-favorable Anti PD-1/PD-L1 tienen menos toxicidad que anti CTLA-4 Y además, en el caso de los anti PD-1, más eficacia
D+T D+T+antiPD1 Hu-Lieskovan 2015 Sci Trans Med
DABRAFENIB+TRAMETINIB+MEDI4736 (anti PD-L1) Fase Ib Ribas ASCO 2015
DABRAFENIB+TRAMETINIB+PEMBROLIZUMAB (KEYNOTE-022) Ribas ASCO 2016
VEMURAFENIB+COBIMETINIB+ATEZOLIZUMAB Atezo start date a Unconfirmed per RECIST v1.1. Data cutoff: June 15, 2016. Sullivan SMR 2016 24
Maximum Reduction in Sum of Longest Diameters From Baseline, % COBIMETINIB+ATEZOLIZUMAB Best overall response (confirmed, RECIST v1.1) 40 44 28 BRAF mutant BRAF WT 20 17 15 0-20 1-1 -2-5 -9-13 -40-38 -39-45 -45-60 -56-56 -80-80 -80-100 -100-100 15 (75%) patients experienced tumor reduction 2 (10%) patients with confirmed PRs had complete disappearance of target lesions Data cutoff: July 12, 2016. Infante SMR 2016 25
VAMOS A HACER UNOS FASES III DE LOS BUENOS, BUENOS CÓMO ME CONOCES! DC comics
T-VEC Chen and Mellman Immunity 2013
T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce Local and Systemic Effects Local Effect: Virally-Induced Tumor Cell Lysis Selective viral replication in tumor tissue Tumor cells rupture for an oncolytic effect Systemic Effect: Tumor-Specific Immune Response Systemic tumor-specific immune response Death of distant cancer cells Andtbacka RHJ et al. Annals of Surgical Oncology 2014; 21(suppl 1; abstr 52) and oral presentation at SSO 2014 Annual Meeting, March 12 15, Phoenix, Arizona
Percentage Change from Baseline Best Change in Overall Tumor Area From Baseline 600 400 200 100 75 50 25 0 25 50 75 100 600 400 200 100 75 50 25 0 25 50 75 100 Talimogene Laherparepvec + Ipilimumab (N = 38) 35,7% (ipi 3 mg + TVEC) Stage IIIb (N = 1) Stage IIIc (N = 8) Stage IV M1a (N = 8) Stage IV M1b (N = 11) Stage IV M1c (N = 10) Ipilimumab (N = 33) Stage IIIb (N = 5) Stage IIIc (N = 7) Stage IV M1a (N = 8) Stage IV M1b (N = 2) Stage IV M1c (N = 11) 17.5% (ipi 3 mg) Chesney ESMO 2016 29
MASTERKEY-265: A phase 1b/3 study of T-VEC + pembrolizumab Long ASCO 2016
ipilimumab Pembrolizumab Nivolumab Epacadostat Chen and Mellman Immunity 2013
IMMUNOCHECKPOINT COMBINATION Ribas 2012 NEJM
CA209-067: Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Stratify by: Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Tumor PD-L1 expression* BRAF mutation status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression** or unacceptable toxicity N=315 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. **Patients could have been treated beyond progression under protocol-defined circumstances. Wolchok 2016 ASCO
Progression-free Percentage Survival of PFS (%) Progression-Free Survival (Intent-to-Treat Population) 100 90 80 70 60 50 NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) 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)* 0.55 (0.43 0.76)* -- HR (95% CI) vs. NIVO 0.76 (0.60 0.92)** -- -- *Stratified log-rank P<0.00001 vs. IPI 49% 46% **Exploratory endpoint 40 30 42% 39% 20 10 Number of patients at risk: Nivolumab + Ipilimumab Nivolumab Ipilimumab 0 18% 0 3 6 9 12 15 18 21 24 27 314 316 315 NIVO+IPI NIVO IPI 219 177 137 174 148 78 156 127 58 PFS per Investigator (months) 133 114 46 126 104 40 103 94 25 14% 48 46 15 8 8 3 0 0 0 Database lock Nov 2015 Wolchok 2016 ASCO 34
Percentage of PFS Percentage of PFS Progression-free Survival by Tumor PD-L1 Expression 100 Tumor PD-L1 Expression Level <5% 100 Tumor PD-L1 Expression Level 5% 90 NIVO + IPI (N=210) NIVO (N=208) IPI (N=202) 90 NIVO + IPI (N=212) NIVO (N=218) IPI (N=215) 80 Median PFS, months (95% CI) 11.1 (8.0 22.2) 5.3 (2.8 7.1) 2.8 (2.8 3.1) 80 Median PFS, months (95% CI) NR (9.7 NR) 22.0 (8.9 NR) 3.9 (2.8 4.2) 70 HR (95% CI) vs NIVO 0.74 (0.58 0.96)* 70 HR (95% CI) vs. NIVO 0.87 (0.54 1.41)* 60 *Exploratory endpoint 60 *Exploratory endpoint 50 50 40 40 30 30 20 10 0 Number of patients at risk: NIVO + IPI NIVO IPI 0 3 6 9 12 15 18 21 24 27 210 208 202 NIVO + IPI NIVO IPI 142 108 82 113 89 45 101 75 34 PFS (months) 86 69 26 81 62 22 69 55 12 31 29 7 5 7 0 0 0 0 20 10 0 Number of patients at risk: NIVO + IPI NIVO IPI 0 3 6 9 12 15 18 21 24 27 68 80 75 NIVO + IPI NIVO IPI 53 57 40 44 51 21 39 45 17 PFS (months) 33 39 14 31 37 12 22 36 8 13 16 6 3 1 2 0 0 0 For the original PD-L1 PFS analysis, the descriptive hazard ratio comparing NIVO+IPI vs NIVO was 0.96, with a similar median PFS in both groups (14 months) Database lock Nov 2015 Wolchok 2016 ASCO 35
Response to Treatment by Tumor PD-L1 Expression* NIVO+IPI NIVO IPI PD-L1 ( 5%) PD-L1 (<5%) ORR, % (95% CI) 72.1 (59.9 82.3) Median Duration of Response (months) ORR, % (95% CI) 54.8 (47.8 61.6) 57.5 (45.9 68.5) 21.3 (12.7 32.3) NR 20.7 NR 41.3 (34.6 48.4) 17.8 (12.8 23.8) Median Duration of Response (months) NR 22.3 18.2 *Pre-treatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated BMS/Dako assay). Database lock Nov 2015 Wolchok 2016 ASCO 36
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 95.8 56.5 84.0 19.8 85.9 27.0 38.7 30.7 10.5 7.3 15.4 13.5 Treatment-related death* 0 0.3 0.3 68.8% 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 Wolchok 2016 ASCO 37
EN EL ENSAYO CHECKMATE067, LA ORR DE IPI+NIVO ERA APROX 57% EN EL ENSAYO KEYNOTE006, LA ORR DE PEMBRO ERA APROX 37%
EN EL ENSAYO CHECKMATE067, LA TASA DE GRADO 3-4 PARA IPI+NIVO ERA APROX 57%
ENSAYO CHECK-MATE 511 MELANOMA ESTADIO IV O IRRESECABLE PRIMER LÍNEA DE TRAATMIENTO INDEPENDIENTE DE BRAF NO UVEAL NIVOLUMAB 1 MG/KG + IPILIMUMAB 3 MG/KG/ 3 SEMANAS 1:1 NIVOLUMAB 3 MG/KG + IPILIMUMAB 1 MG/KG/ 3 SEMANAS SEGUIDO DE NIVOLUMAB 480 MG DT/4 SEMANAS SEGUIDO DE NIVOLUMAB 480 MG DT/4 SEMANAS
Indoleamina 2,3 deoxigenasa (IDO) Para Qué sirve IDO? Participa en el metabolismo del triptófano (aa esencial) Se expresa en endotelio placentario y pulmonary y células dendríticas Participa en la tolerancia immune Disminuye la cantidad de triptófano Muchos tumors favorecen la expression de IDO Moon 2015 Journal of Imm Cancer
SMR, O. Hamid, November 21, 2015
SMR, O. Hamid, November 21, 2015
SMR, O. Hamid, November 21, 2015
NOS QUEDAN MUCHOS CHECK- POINTS POR EXPLORAR Márquez-Rodas 2016 Ann Trans Med
CONCLUSIONES La resistencia primaria a la inmunoterapia es un hecho que impide que se beneficien todos los pacientes Existen multiples puntos en el ciclo de la inmunidad del cancer que: Inhiben el potencial de nuestro Sistema immune Pero que pueden ser farmacológicamente modulados Única combinación probada (fase III) y aprobada: ipilimumab+nivolumab Toxicidad muy significativa Pendientes de multiples fase III que exploran otras combinaciones
Qué combinación será la de elección? DC comics