Largos supervivientes con Inmunoterapia: melanoma como prueba de concepto en metastásico y adyuvancia. Dra. Ainara Soria Rivas Oncología Médica

Transcripción

1 Largos supervivientes con Inmunoterapia: melanoma como prueba de concepto en metastásico y adyuvancia Dra. Ainara Soria Rivas Oncología Médica

2 INMUNOVIGILANCIA e INMUNOEDICIÓN Dunn et al, Immunity, 2004

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4 Sharma P, et al. Science. 2015;348:56-61.

5 DATOS DE SUPERVIVENCIA A LARGO PLAZO

6 La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global. 1. Impacta de modo marginal en SG. 2. Sólo ha beneficiado subgrupos específicos de enfermos. 3. Ha conseguido aumentar supervivencia global por encima de los 24 meses. 4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.

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8 Estudios antipd-1 tras progresión a Ipilimumab + ibraf CA Nivolumab D Angelo SP. SMR 2014 N 540 KEYNOTE-002 Pembrolizumab Ribas A. SMR 2014

9 OS (%) CA OS in All Treated Patients Censored at Start of Subsequent Anti- PD-1 Therapy in ICC Group (n = 268) ICC (n = 102) Events Median OS, months (95% CI) 16.4 (12.9, 20.3) HR (95% CI) 0.81 (0.59, 1.11) 11.8 (9.9, 14.4) % ICC 29% Number of Patients at Risk Time (Months) ICC In this post-hoc analysis, median OS was 4.6 months longer in vs ICC 9

10 KEYNOTE-002 Ribas A, et al. Lancet Oncol 2015

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12 KEYNOTE 001: Resultados finales

13 Robert C, et al. N Engl J Med 2015

14 ACTUALIZACIÓN DE SUPERVIVENCIA GLOBAL KEYNOTE-006

15 CA : Study Design CheckMate 067 N=314 1 mg/kg + 3 mg/kg Q3W for 4 doses then 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: BRAF status AJCC M stage Tumor PD-L1 expression <5% vs 5%* N=316 3 mg/kg Q2W + -matched placebo Treat until progression or unacceptable toxicity Randomized, double-blind, phase III study to compare + or alone to alone* N=315 3 mg/kg Q3W for 4 doses + -matched placebo Database lock: Sept 13, 2016 (median follow-up ~30 months in both -containing arms) *The study was not powered for a comparison between and + Larkin J. NEJM 2015 Larkin J. ESMO

16 Grob JJ. ESMO 2017

17 KEYNOTE 006: LARGAS SUPERVIVENCIAS TRAS TRATAMIENTO

18 KEYNOTE 006: LARGAS SUPERVIVENCIAS TRAS TRATAMIENTO

19 KEYNOTE 001 DFS de enfermos con CR que discontinuaron Pembrolizumab DFS 24 meses: 89,9% Robert C. JCO Dec 2017

20 CheckMate 069/067: Pooled 3-Year Analysis Patients Alive at 3 Years On and Off Treatment + (n = 224) a (n = 149) (n = 114) 17.4% n = % n = % n = % n = % n = % n = % n = % n = % n = 36 Still on treatment Off treatment and never received subsequent systemic therapy Off treatment and received subsequent systemic therapy In the + arm, median duration of response was not reached with 69% of patients alive and remaining treatment free a arm was from CheckMate 067 study only Postow M. STIC 2017

21 La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global. 1. Impacta de modo marginal en SG. 2. Sólo ha beneficiado subgrupos específicos de enfermos. 3. Ha conseguido aumentar supervivencia global por encima de los 24 meses. 4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.

22 PAPEL EN ADYUVANCIA

23 La adyuvancia con inmunoterapia en melanoma. 1. Debe considerarse experimental, dada la inmadurez de sus datos. 2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos. 3. No ha demostrado aumentar supervivencia global. 4. El interferon alfa debe seguir considerándose un estándar de tratamiento.

24 287 pacientes Estadios IIB,IIC,III Seguimiento 6,9 años SLR SG RFS 0.72 vs 0.98 y HR = 0.61 (P =.0023) OS 3.82 vs 2.78 y HR = 0.67 (P =.0237) J Clin Oncol Jan;14(1):7-17.

25 NEJM 2016

26 EORTC 18071/CA : Study Design Randomized, double-blind, phase 3 study evaluating the efficacy and safety of ipilimumab in the adjuvant setting for high-risk melanoma High-risk, stage III, completely resected melanoma N = 951 N = 475 R N = 476 INDUCTION Ipilimumab 10 mg/kg Q3W 4 INDUCTION Placebo Q3W 4 MAINTENANCE Ipilimumab 10 mg/kg Q12W up to 3 years MAINTENANCE Placebo Q12W up to 3 years Stratification factors Week 1 Week 12 Week 24 Treatment up to a maximum of 3 years, or until disease progression, intolerable toxicity, or withdrawal Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC 4 positive lymph nodes) Regions (North America, European countries, and Australia) Enrollment Period: June 2008 to July 2011 Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization. 26

27 Patients Alive and Without Recurrence (%) RECURRENCE FREE SURVIVAL (per IRC) Ipilimumab Placebo Events/patients 264/ /476 HR (95% CI) a 0.76 (0.64, 0.89) Log-rank P value a Median RFS, months (95% CI) 41% 30% O N Number of patients at risk (19.3, 37.2) 17.1 (13.6, 21.6) a Stratified by stage provided at randomization. CI = confidence interval. Years Ipilimumab Placebo

28 Patients Alive (%) SUPERVIVIENCIA GLOBAL Ipilimumab Placebo Deaths/patients 162/ /476 HR (95.1% CI) a 0.72 (0.58, 0.88) Log-rank P value a % 54% O N Number of patients at risk a Stratified by stage provided at randomization. Years Ipilimumab Placebo

29 SAFETY SUMMARY Ipilimumab (n = 471) Any Grade Grade 3/4 Any grade Placebo (n = 474) Grade 3/4 Any AE, % Treatment-related AE, % Treatment-related AE leading to discontinuation, % Any immune-related AE, % o o 5 patients (1.1%) in the ipilimumab group 3 patients with colitis (2 with gastrointestinal perforations) 1 patient with myocarditis 1 patient had multiorgan failure with Guillain-Barré syndrome No deaths related to study drug in the placebo group

30 Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238) Jeffrey Weber, 1 Mario Mandala, 2 Michele Del Vecchio, 3 Helen Gogas, 4 Ana M. Arance, 5 C. Lance Cowey, 6 Stéphane Dalle, 7 Michael Schenker, 8 Vanna Chiarion-Sileni, 9 Ivan Marquez-Rodas, 10 Jean-Jacques Grob, 11 Marcus Butler, 12 Mark R. Middleton, 13 Michele Maio, 14 Victoria Atkinson, 15 Paola Queirolo, 16 Veerle de Pril, 17 Anila Qureshi, 17 James Larkin, 18 * Paolo A. Ascierto 19 * 1 NYU Perlmutter Cancer Center, New York, New York, USA; 2 Papa Giovanni XIII Hospital, Bergamo, Italy; 3 Medical Oncology, National Cancer Institute, Milan, Italy; 4 University of Athens, Athens, Greece; 5 Hospital Clínic de Barcelona, Barcelona, Spain; 6 Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; 7 Hospices Civils de Lyon, Pierre Bénite, France; 8 Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9 Oncology Institute of Veneto IRCCS, Padua, Italy; 10 General University Hospital Gregorio Marañón, Madrid, Spain; 11 Hôpital de la Timone, Marseille, France; 12 Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13 Churchill Hospital, Oxford, United Kingdom; 14 Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15 Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; 16 IRCCS San Martino-IST, Genova, Italy; 17 Bristol-Myers Squibb, Princeton, New Jersey, USA; 18 Royal Marsden NHS Foundation Trust, London, UK; 19 Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study. 30

31 Patients with highrisk, completely resected stage IIIB/IIIC or stage IV melanoma Stratified by: CA : Study Design Enrollment period: March 30, 2015 to November 30, 2015 n = 453 n = 453 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells 3 mg/kg IV Q2W and placebo IV Q3W for 4 doses then Q12W from week 24 Stage IIIB, IIIC, or stage IV melanoma by the American Joint Committee 1:1 on Cancer 2009 classification, 7th edition Complete regional lymphadenectomy or resection was required within 12 weeks of randomization Acral or Mucosal Melanomas were allowed 10 mg/kg IV Q3W for 4 doses then Q12W from week 24 and placebo IV Q2W Follow-up Maximum treatment duration of 1 year Primary endpoint: RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death Secondary endpoints OS, Safety and tolerability, RFS by PD-L1 tumor expression, HRQoL Current interim analysis: Primary endpoint (RFS), safety, and HRQoL ;DMFS (exploratory) Duration of follow-up: minimum 18 months; 360 events ESMO 2017

32 CARACTERÍSTICAS BASALES (n = 453) (n = 453) Median age, years Male, % Stage, IIIB+IIIC, % Macroscopic lymph node involvement (% of stage IIIB+IIIC) Ulceration (% of stage IIIB+IIIC) Stage IV, % M1c without brain metastases (% stage IV) PD-L1 expression 5%, % BRAF mutation, % LDH ULN, % Most of the patients had cutaneous melanoma (85%), and 4% had acral and 3% had mucosal melanoma All 905 patients are off treatment; median doses were 24 (1-26) in the group and 4 (1-7) in the group 397 patients completed 1 year of treatment (61% of the group and 27% of the group) ESMO 2017

33 RFS (%) Primary Endpoint: RFS Events/patients 154/ / Median (95% CI) NR NR (16.6, NR) 90 HR (97.56% CI) 0.65 (0.51, 0.83) % Log-rank P value 66% < % 53% Months Number of patients at risk ESMO 2017

34 RFS (%) RFS (%) Subgroup Analysis of RFS: PD-L1 Expression Level PD-L1 Expression Level <5% PD-L1 Expression Level 5% Events/patients 114/ /286 Events/patients 31/152 57/154 Median (95% CI) NR 15.9 (10.4, NR) Median (95% CI) NR NR 100 HR (95% CI) 0.71 (0.56, 0.91) 100 HR (95% CI) 0.50 (0.32, 0.78) % % % % Number of patients at risk Months Number of patients at risk Months ESMO 2017

35 RFS (%) RFS (%) Subgroup Analysis of RFS: Disease Stage Stage III Stage IV Events/patients 120/ /366 Events/patients 33/82 43/87 Median (95% CI) NR NR (16.6, NR) Median (95% CI) NR (15.9, NR) 16.8 (8.5, NR) 100 HR (95% CI) 0.65 (0.52, 0.83) 100 HR (95% CI) 0.70 (0.45, 1.10) % % % 50 58% Months Months Number of patients at risk Number of patients at risk ESMO 2017

36 RFS (%) RFS (%) Subgroup Analysis of RFS: BRAF Mutation Status BRAF Mutant BRAF Wild type Events/patients 63/187 84/194 Events/patients 67/ / Median (95% CI) NR NR (16.1, NR) HR (95% CI) 0.72 (0.52, 1.00) Median (95% CI) NR 16.6 (12.3, NR) HR (95% CI) 0.58 (0.43, 0.79) % % % % Number of patients at risk Months Number of patients at risk Months ESMO

37 DMFS (%) Exploratory Endpoint: DMFS for Stage III Patients % 73% Events/patients 93/ /366 Median (95% CI) NR NR HR (95% CI) 0.73 (0.55, 0.95) Log-rank P value Number of patients at risk Months ESMO 2017

38 Safety Summary (n = 452) (n = 453) AE, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Any AE 438 (97) 115 (25) 446 (98) 250 (55) Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46) Any AE leading to discontinuation Treatment-related AE leading to discontinuation 44 (10) 21 (5) 193 (43) 140 (31) 35 (8) 16 (4) 189 (42) 136 (30) There were no treatment-related deaths in the group There were 2 (0.4%) treatment-related deaths in the group (marrow aplasia and colitis), both >100 days after the last dose ESMO 2017

39 Treatment-Related Select Adverse Events (n = 452) (n = 453) AE, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Skin 201 (44.5) 5 (1.1) 271 (59.8) 27 (6.0) Gastrointestinal 114 (25.2) 9 (2.0) 219 (48.3) 76 (16.8) Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (10.8) Pulmonary 6 (1.3) 0 11 (2.4) 4 (0.9) Renal 6 (1.3) 0 7 (1.5) 0 Hypersensitivity/infusion reaction 11 (2.4) 1 (0.2) 9 (2.0) 0 Endocrine Adrenal disorder 6 (1.3) 2 (0.4) 13 (2.9) 4 (0.9) Diabetes 2 (0.4) 1 (0.2) 1 (0.2) 0 Pituitary disorder 8 (1.8) 2 (0.4) 56 (12.4) 13 (2.9) Thyroid disorder 92 (20.4) 3 (0.7) 57 (12.6) 4 (0.9) ESMO 2017

40 CHECKMATE-915 Melanomas III-B or III-C or III-D AJCC 8th edition Primary endpoint: RFS LUMAB + LIMUMAB LUMAB

41 La adyuvancia con inmunoterapia en melanoma. 1. Debe considerarse experimental, dada la inmadurez de sus datos. 2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos. 3. No ha demostrado aumentar supervivencia global. 4. El interferon alfa debe seguir considerándose un estándar de tratamiento.

42 ALGUNA PREGUNTA??? MUCHAS GRACIAS