Organizado por: Fundación para el progreso de la oncología en Cantabria, FUPOCAN

Transcripción

1 Coordinador Científico: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander Organizado por: Fundación para el progreso de la oncología en Cantabria, FUPOCAN

2 Anti-CTLA4 más anti-pd1 en melanoma avanzado, un nuevo estándar? Eva Muñoz Couselo, MD, PhD Oncología médica Hospital Vall d Hebrón, Barcelona

3 Checkpoint Inhibitors and Melanoma: Fase III trials 1st line of treatment a NIVO PEMBRO NIVO + IPI Median PFS, mo IPI Q2W Q3W ,9 2.8 b,1 CheckMate 66 3 (3 mg/kg, BRAF CheckMate 674 (3 mg/kg) WT) KEYNOTE 6 5 (1 mg/kg) not approved dose CheckMate 67 4,9 (ipi 3 mg/kg + nivo 1mg/kg) 1-year OS 47% b,2 73% 9 7% 74% 74% 68% Long-term survival 5y 2y 2y 2y 2y (18%) b,6,7 (58%) 8 (59%) 9 (55%) 9 (64%) 9 a Data from separate, noncomparative trials; a cross-trial comparison is not intended. b In combination with dacarbazine. IPI = ipilimumab; Mo = months; NA = not available; NIVO = nivolumab; OS = overall survival; PEMBRO = pembrolizumab; PFS = progressionfree survival; Q2W = every 2 weeks; Q3W = every 3 weeks; y = years. 1. Wolchok J, et al. Presented at ASCO Robert C, et al. N Engl J Med. 211;364: Robert C, et al. N Engl J Med. 215;372: Larkin J, et al. N Engl J Med. 215;373: Robert C, et al. N Engl J Med. 215;372: Schadendorf D, et al. J Clin Oncol. 215;33: Maio M, et al. J Clin Oncol. 215;33: Atkinson V, et al. Presented at SMR Schachter et al. Presented at ASCO 216, 9. Larkin et al.presented at AACR 217

4 Overall Survival (%) Los fármacos inhibidores de immunocheckpoints demuestran una supervivencia al largo plazo en pacientes afectos de melanoma metastásico 1 9 IPI (Pooled analysis) N=314 N=21 N=241 N= 152 N=17 NIVO Monoterapia (Fase 1 CA29-3) 2 PEMBRO Monoterapia (Fase 1 KEYNOTE 1) 3 NIVO Monoterapia (Fase 3 Checkmate 66) 4 PEMBRO Monoterapia (Fase 3 KEYNOTE 6) 5 IPI + NIVO Combinación (Fase 3 Checkmate 67) N=1, Years 1. Schadendorf et al. J Clin Oncol 215;33: ; 2. Current analysis; 3. Robert et al. ASCO 216, 4. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress, 4. 6, 5., 6. Larkin et al. AACR 217, 5.

5 COMBINATIONS: THE FUTURE? 7% Nivo Overall Survival Metastatic Melanoma<br />1-year OS Phase III Studies 73% Nivo + Ipi (Ph III) 64% Nivo + Ipi (Ph III) 57 7% Nivo (Ph III) C+V 3y = 37.2% D+T 3y = 45% C+V 4y (pre-treated) = 35.9% 55% 44% 4% 28% Dab + Tram (Ph II) Adapted from Georgina Long

6 COMBINACIONES Inmunoterapia y MELANOMA Anti-CTLA4 + Anti-PD-1 Anti-PD1 + terapia citoquina Anti-PD1/PD-L1 + nuevos agentes inmunoterápicos y otras terapias dirigidas ASCO 215

7 Checkpoint inhibition: Balance between inhibitory and stimulatory receptors dictates T cell priming T cell targets for modulating activity Mellman I, et al. Nature 211

8 INMUNOTERAPIA Co-primary endpoints: Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone* CheckMate CA29-67: 67: Study Study Design PFS and OS (intent-to-treat population) Secondary and exploratory endpoints: ORR by RECIST v1.1 Stratify by: Unresectable or BRAF status Metatastic Melanoma Randomize AJCC M stage Efficacy Previously by untreated tumor PD-L1 1:1:1 expression Tumor PD-L1 level 945 patients expression <5% vs 5%* 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 Safety profile (in patients who received 1 dose of study drug) Treat until progression or unacceptable toxicity Current analysis 3 rd April Dr. Larkin AACR 217: IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo 31 5% BRAF mutados N=315 (1ª línea pura) (99% power 36 1% LDH to detect elevada a HR of.65 for each NIVO-containing arm vs IPI) 23 6% PD-L1 alto expresor Database lock: Sept 13, 216 (median follow-up -> However, the actual number of deaths was 28% ~3 months lower in both than NIVO-containing anticipated arms) (95% power to detect a HR of.65 vs IPI) *The study was not powered for a comparison between NIVO and NIVO+IPI Per protocol, a total of 644 deaths were projected to occur at 28 months The study was not powered for a comparison between NIVO+IPI and NIVO 3 1. Wolchok JD, et al. Presented at ASCO 213; abstract Sharma P, et al. Science. 215;348:56-61, 3. Postow et al. N Engl. J Med 215, 4. Larkin et al. AACR 217

9 Cuáles son los mayores beneficios del COMBO Ipilimumab + Nivolumab en melanoma metastásico?

10 1. Claro racional biológico y consistencia de los datos a lo largo de los diferentes ensayos clínicos Rationale PD-1 and CTLA-4 are nonredundant immune checkpoints in T cell differentiation and function Anti-tumor synergy demonstrated in several murine models Both agents are active in metastatic melanoma

11 Ensayos clínicos con NIVO 1mg/kg + IPI 3mg/kg Study Population Results Phase 1 study (CA29-4) Treated and untreated melanoma BRAF WT/MT ORR with NIVO+IPI up to 53% CR with NIVO+IPI of 18% 2-year OS rate of 79% 3 year OS rate of 68% Phase 2 study (CheckMate 69) Untreated melanoma BRAF WT/MT Compared with IPI alone, NIVO+IPI significantly improved ORR and PFS ORR of 59% with NIVO+IPI vs 11% with IPI alone Higher OS rate at 2 years: 69% for NIVO+IPI vs. 53% for IPI alone Treatment-related grade 3-4 Aes: 54% with NIVO+IPI vs 24% with IPI alone Phase 3 study (CheckMate 67) Untreated melanoma BRAF WT/MT Nivo alone and NIVO+IPI significantly improves OS, PFS and ORR vs IPI alone ORR of 59% with NIVO+IPI vs 19% with IPI alone Higher OS rate at 2 years: 64% for NIVO+IPI vs. 45% for IPI alone OS, PFS and ORR are numerically greater with NIVO+IPI vs NIVO Treatment-related grade 3-4 Aes: 58% with NIVO+IPI vs 27% with IPI alone Most AES managed and resolved in 3-4 weeks (85-1%) ORR 7% for those patients who discontinued NIVO+IPI for toxicity Sznol et al. ASCO 214Larkin Let al. N Engl.J Med 215; Postow et al. N Engl. J Med 215; Postow et al. AACR 216; Larkin et al. AACR 217

12 Best Reduction From Baseline in Target Lesion (%) 2. Tasas de respuesta más consistentes, elevadas y más duraderas que anti-pd1 en monoterapia NIVO + IPI Median change: -7% NIVO+IPI (ORR 59%) (N=314) IPI Median change: +5% NIVO IPI (ORR 11%) (N=316) (N=315) ORR, % (95% CI)* 58.9 ( ) 44.6 ( ) 19. ( ) Best25 overall response % Response To Treatment Nivolumab ORR 4% Complete response Partial response Stable -25 disease Progressive disease Unknown Anti-PD1: tiempo medio de respuesta 2 8 meses -75 Median duration of response, months (95% CI) NR (NR NR) 31.1 (31.1 NR) 18.2 (8.3 NR) -1 *By RECIST v1.1; NR = not reached. * = confirmed responder Updated Response To Treatment Patients CheckMate 67 At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively Database lock: Sept 13, 216, minimum f/u of 28 months Atkinson V, et al. SMR 215, Postow et al. AACR 216, Schachter et al. ASCO 216, Wolchok JD, et al. ASCO 215, Larkin et al. AACR 217 5

13 Progression-free Percentage Survival of PFS (%) 3. Doble PFS comparado con anti-pd1 en monoterapia Updated Progression-Free Survival CheckMate Median PFS, mo (95% CI) HR (95% CI) vs. IPI HR (95% CI) vs. NIVO 5% 43% NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) 11.7 ( ).42 (.34.51).76 (.62.94) 43% 37% 6.9 ( ).54 (.45.66) 2.9 ( ) NIVO+IPI 1 NIVO 18% IPI 12% Months Patients at risk: NIVO+ IPI NIVO IPI Database lock: Sept 13, 216, minimum f/u of 28 months 8 Larkin et a 217 AACR Anual Meeting

14 4. OS a 2 y 3 años nunca vistas en melanoma, incluso en aquellos pacientes que discontinúan por toxicidad CheckMate 29-4

15 Overall Percentage Survival of PFS (%) CheckMate 67 Overall Survival NIVO+IPI NIVO IPI 73% 74% 67% Median OS, mo (95% CI) HR (98% CI) vs. IPI HR (95% CI) vs. NIVO Months Patients at risk: NIVO+IPI NIVO IPI % 59% 45% NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) NR.55 (.42.72)*.88 ( ) Reducción de riesgo de muerte del 12% a favor de IPI+NIVO NR (29.1 NR).63 (.48.81)* 2. ( ) *P<.1 Database lock: Sept 13, 216, minimum f/u of 28 months 7 Larkin et al presented at 217 AACR Annual Meeting

16 5. Menor necesidad de tratamientos de 2ª línea y mayor intervalo de tiempo hasta llegar a ella Subsequent Therapies: All Randomized Patients NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71) Systemic therapy 1 (32) 14 (44) 196 (62) Anti-PD-1 agents 3 (1) 32 (1) 132 (42) Anti-CTLA-4 19 (6) 83 (26) 12 (4) BRAF inhibitors 4 (13) 57 (18) 68 (22) MEK inhibitors 3 (1) 38 (12) 39 (12) Investigational agents** 8 (3) 6 (2) 15 (5) Median time to subsequent systemic therapy, mo (95% CI) NR (NR NR) 26.8 (18. NR) 8.5 ( ) 2 year % of pts free of subsequent therapies *Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies) **Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors CheckMate 67 8 Larkin presented at 217 AACR Annual Meeting

17 6. Claro beneficio en todos los subgrupos de pacientes Subgroup PFS and OS Subgroup Analyses (All Randomized Patients) Descriptive comparison between NIVO+IPI and NIVO Patients Unstratified Hazard Ratio Unstratified Hazard Ratio (95% CI) NIVO+IPI NIVO PFS OS PFS OS Overall <65 years years BRAF Mutant BRAF Wild-type ECOG PS = ECOG PS = M/M1a/M1b M1c LDH ULN LDH > ULN LDH > 2 x ULN PD-L1 5% PD-L1 <5% CheckMate 67 1 NIVO+IPI NIVO 2 1 NIVO+IPI NIVO 2 9 Larkin et al presented at 217 AACR Annual Meeting

18 OS (%) OS (%) 7. Beneficio incluso en aquellos pacientes PD-L1 bajo expresores OS (%) OS (%) CheckMate Similar OS by Outcomes Tumor PD-L1 Were Expression, Observed 5% at Cutoff a 1% Cutoff PD-L1 Expression Level <5% <1% PD-L1 PD-L1 Expressio Expression Expression Leve 5% Level >5% Level 1% >1% <1% PD-L1 NIVO+IPI NIVO+IPI NIVOIPI IPI Median Median OS, mo OS, mo NR NR NR (95% (95% CI) CI) (31.8 NR) (26.5 NR) (23.1 NR) (13. NR) ( ) ( ) HR (95% CI).84 HR (95% CI).74 vs NIVO ( ) vs NIVO ( ) 63% 6% 49% 55% 41% 41% NIVO+IPI IPI % PD-L1 NIVO+IPI NIVO+IPI NIVO IPI IPI Median Median OS, mo OS, mo 28.9 NR NR 22.1 (95% CI) NR (18.1 NR) (95% CI) ( ) HR (95% CI) 1.5 HR (95% CI) 1.3 vs NIVO ( ) vs NIVO ( ) 2 1 ORR of 56.2% for NIVO+IPI and 42.3% for NIVO 1 2 ORR of 73.5% for NIVO+IPI and 58.8% for NIVO 1 ORR of 54.5% for NIVO+IPI and 35.% for NIVO 1 ORR of 65.2% for NIVO+IPI and 55.% for NIVO Months Months Patients at risk: Patients at risk: NIVO+IPI NIVO+IPI Months Months NIVO NIVO Patients at risk: Patients at risk: NIVO IPI While a greater PFS benefit for NIVO+IPI relative to NIVO was observed in low PD-L1 expressors, NIVO+IPI resulted in clinically meaningful improvements in ORR regardless of PD-L1 expression level % 68% 54% 67% 67% 48% IPI NIVO+IPI NIVO IPI Larkin et al presented at 217 AACR Annual Meeting

19 Similar Efficacy Regardless of Tumor PD-L1 Status (All Randomized Patients, NIVO + IPI Ph II CheckMate 69) 58% 55% 48% 48% 67% 6% Database lock Jan 215 Database lock Feb 216 Database lock Feb 216 *Of the 94 all randomized patients treated with the combination NIVOLUMAB + IPILIMUMAB, 8 (85%) had quantifiable PD-L1 expression. 3% had PD-L1 tumor expression 5% and 7% had PD-L1 tumor expression <5%. Postow et al. AACR 216

20 OS (%) OS (%) 8. Beneficio también en aquellos pacientes BRAF mutados y/o en aquellos con LDH elevada OS in Patients with BRAF Wild-type and Mutant Tumors BRAF Wild-type NIVO+IPI NIVO IPI BRAF Mutant NIVO+IPI NIVO IPI Median, mo (95% CI) NR (27.6 NA) NR (25.8 NR) 18.5 ( ) Median, mo (95% CI) NR NR (26.4 NR) 24.6 ( ) 1 HR (95% CI) vs NIVO.97 ( ) HR (95% CI) vs NIVO.71 ( ) % 57% % 62% 51% 3 42% 3 Patients at risk: 2 NIVO+IPI 1 NIVO IPI Months NIVO+IPI Patients at risk: 2 NIVO+IPI 1 NIVO IPI Months NIVO+IPI NIVO NIVO IPI IPI Larkin et al presented at 217 AACR Annual Meeting

21 Efficacy of Nivolumab Plus Ipilimumab Combination in Patients With Advanced Melanoma and Elevated Serum Lactate Dehydrogenase: a Pooled Analysis

22 9. Claro beneficio en pacientes con M1 SNC

23 9. Claro beneficio en pacientes con M1 SNC II

24 1. También beneficio en pacientes con melanoma de mucosas Mucosa mediana PFS: NIVO: 3. meses IPI + NIVO: 5.9 meses IPI: 2.7 meses Cutáneo mediana PFS: NIVO: 6.2 meses IPI + NIVO: 11.7 meses IPI: 3.9 meses

25 11. BONUS TRACK, IPI low doses CHECKMATE 511: Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination With Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination With Ipilimumab 3 mg/kg in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma Active, No Longer Recruiting Latest Information Update: 2 Apr 217

26 12. La unión hace la fuerza y no la secuencia Ipilimumab 2ª línea: 9 meses de mediana de SG adicional en pacientes pretratados con anti-pd1 CheckMate 66: 57 pacientes pretratados con Nivolumab recibieron Ipilimumab en 2ª línea 1. Hodi et al. N Engl J Med. 21;363: Atkinson et al. Presentado en el Society Melanoma Research 215, San Francisco, EE. UU. 3. Schadendorf et al. J Clin Oncol. 215;33: Bowyer et al. Br J Cancer. 216;114:184-9.

27 Qué pasa con la toxicidad?

28 Safety Summary CheckMate 67 With an additional 19 months of follow-up, safety was consistent with the initial report 1 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 death, n (%) 2 (.6) a 1 (.3) b 1 (.3) b Most select AEs were managed and resolved within 3-4 weeks (85 1% across organ categories) ORR was 7.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached a Cardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >1 days after the last treatment. b Neutropenia (NIVO, n=1); colon perforation (IPI, n=1) Larkin J, et al. NEJM 215;373:

29 CheckMate 67 Most Common Treatment-related Select AEs Jedd Wolchok presented at 216 ASCO Annual Meeting

30 Manejo de los efectos adversos INMUNOMEDIADOS Educación del paciente y del personal sanitario que interacciona con él. El paciente debe ser evaluado antes de cada dosis de tratamiento. Laboratorio: TSH, LDH, bioquímica con perfil hepático Repaso de la sintomatología más frecuente. Manejo de efectos adversos en función de la gravedad de los mismos y de los ALGORITMOS establecidos. Inicio precoz de del tratamiento de soporte en todos los eventos adversos y del tratamiento con corticoterapia (en caso de toxicidad moderada/grave) Leve: tratamiento de soporte, monitorización estrecha Moderado: parar el tratamiento, valorar corticoides Grave: discontinuar permanentemente el tratamiento, inicio de corticoides

31 Patients Percentage Probability of PFS Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab plus ipilimumab due to toxicity Number of patients at risk: Discontinued due to an AE Did not discontinue due to an AE NIVO+IPI DC NIVO+IPI no DC (n = 176) (n = 233) 1. Median PFS, months (95% Discontinued CI) Due to AEs 16.7 (1.2, NA) 1.8 (5.9, 23.) HR (99.5% CI).74 (.56,.98), P <.4.9 NIVO+IPI NIVO + IPI % Discontinued due Did not discontinue DC No DC to AEs due to AEs (n = 176) (n = 233).7 (n = 176) (n = 233) Median time to % ORR, % (95% CI) 49.3% response, months (6.8, 75.) (43.6, 56.8) ( ) ( ) % (range) P value for comparison.2.4 Median duration of Best overall response, % 48.4% 45.9% response, months NR NR.3 (range) Complete response On treatment Partial response 5.6 Ongoing response /12 94/117.1 Off treatment among (68) (8) Stable disease First response responders, n/n Progressive 3 disease 6 9 Ongoing 12 response (%) P 27 value = Unable to determine PFS per Investigator (Months) Best Overall Response Time to Response and Durability of Response in Patients Who DC = patients who discontinued due to an AE; no DC = patients who did not discontinue due to an AE; NR = not recorded Median Minimum time follow-up to subsequent Time (Weeks) of 18 systemic months, therapy median was length not of reached follow-up in either = 21.3 group, months with 87% and 71% of patients, respectively, free of systemic treatments at 12 months DC = patients who discontinued due to an AE; NA = not available; no DC = patients who did not discontinue due to an AE Minimum follow-up of 18 months 1. Larkin J et al. N Engl J Med. 215;373: Used with permission by Wolchok JD et al. ASCO Schadendorf, D et al. EADO 216

32 Qué podemos aprender de los diferentes ensayos con los COMBOs de inmunoterapia?

33 217 La combinación IPI+NIVO presenta de manera estadísticamente significativa un mayor beneficio en cuanto a OS y PFS respecto a IPI en pacientes afectos de melanoma metastásico. En un análisis descriptivo: NIVO+IPI obtiene numéricamente un mayor beneficio en cuanto a OS, PFS y ORR vs NIVO Dichos resultados son superiores para IPI+NIVO incluso en aquellos subgrupos de pacientes más relevantes: BRAF mutados, LDH elevada, M1 SNC (ORR 5%), PD-L1 bajo expresores (<5% o <1%): Aunque la curvas de OS son parecidas para la población alta expresora de PD-L1 (>5% o >1%), IPI+NIVO presentó una mayor tasa de ORR vs NIVO independientemente del nivel de expresión de PD-L1 La mediana de duración de respuesta resulta ser mayor para IPI+NIVO El tiempo medio a segunda línea de tratamiento no se ha alcanzado para IPI+NIVO El perfil de toxicidad de IPI+NIVO es consistente en todos los estudios, con un 58% de eventos grado3-4, una tasa de discontinuación del 4% pero un 7% de los pacientes que discontinúan el tratamiento se siguen beneficiando del mismo. El 5-6% precisan tratamiento inmunosupresor, el 85-1% de los efectos adversos se resuelven en 3-4 semanas con tratamiento médico. Larkin Presented et al By presented Jeffrey Weber at 217 at AACR 217 Annual ASCO Annual Meeting Meeting

34 EVOLUCIÓN DEL TRATAMIENTO DEL MELANOMA Previo a 211: - Mantener la calidad de vida de los pacientes - Paliar los síntomas - Minimizar los efectos adversos relacionados con el tratamiento Avances en MELANOMA Ipilimumab 211 Nivolumab 214 Pembrolizumab 214 Nivolumab+ Ipilimumab 215 Vemurafenib 211 Trametinib 213 Dabrafenib 213 Dabrafenib + trametinib 214 Vemurafenib + Cobimetinib 215 Previo a 218: - Aumentar la SUPERVIVENCIA de los pacientes - Mantener la calidad de vida de los pacientes - Paliar los síntomas - Minimizar los efectos adversos relacionados con el tratamiento

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