Novo Algoritmo de Tratamento para o Manejo de Melanoma Metastático

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1 Novo Algoritmo de Tratamento para o Manejo de Melanoma Metastático Dr Antonio C Buzaid Diretor, Centro Oncológico Antonio Ermírio de Moraes, Beneficência Portuguesa de São Paulo Membro do Comitê Gestor, Centro de Oncologia Dayan-Daycoval, Hospital Israelita Albert Einstein

2 O que há de novo em terapia alvo?

3 Dabrafenibe + Trametinibe versus Dabrafenibe OS COMBI-d Sobrevida Global População com intenção de tratamento Dabrafenibe + Trametinibe (N=211): não alcançou a mediana 1, Probabilidade de Sobrevida Global,9,8,7,6 Dabrafenibe apenas (N=212): não alcançou a mediana,5,4,3 Hazard ratio,,63 (IC 95%,,42-,94) P=,2,2,1, Meses desde a Randomização Nº pacientes sob risco Dabrafenibe + Trametinibe Dabrafenid apenas Long et al. N Eng J Med 371:1877, 214

4 Dabrafenibe + Trametinibe versus Vemurafenibe OS COMBI-v Dabrafenibe + Trametinibe Pacientes (%) Nº pacientes sob risco Dabrafenibe + Trametinibe Vermurafenibe Vemurafenibe HR,69 IC 95%,53-,89 p =, Meses Robert et al. N Eng J Med 371:1877, 214

5 Sobrevida Global (%) Vemurafenibe + cobimetinibe versus Vemurafenibe OS cobrim 1 Vemurafenibe + cobimetinibe (N=247) Vemurafenibe + placebo (N=248) Hazard ratio,,65 (IC 95%,,42-1,) 1 P=, Meses Nº pacientes sob risco Vemurafenibe + Cobimetinibe Vemurafenibe + Placebo Larkin et al. N Eng J Med 371:1877, 214

6 See the Full Publication in Lancet Oncology See the Full Publication in Lancet Oncology

7 COMBI-MB: Study design (phase 2) Key eligibility criteria Cutaneous melanoma metastic to the brain BRAF V6D/E/K/R mutation positive 2 prior metastatic melanoma systemic treatments No prior BRAFi or MEKi Corticosteroids permitted; stable or decreasing dose only for cohorts A-C S C R E E N I N G BRAF V6E BRAF V6D/K/R BRAF V6D/E/K/ R Cohort A: Interim analysis for futility after 22 patients had assessments Cohort A (n = 76) Asymptomatic Without prior local therapy ECOG PS -1 Cohort B (n = 16) Asymptomatic COMBI-MB: Design (phase 2) With priorstudy local therapy ECOG PS -1 Cohort C (n = 16) Asymptomatic With or without prior local therapy ECOG PS -1 Sabrafenib 15 mg BID + Trametinib 2 mg QD Cohort C (n = 17) Symptomatic With or without prior local therapy ECOG PS -2 Primary endpoint: intracranial response (IR) rate in cohort A a Secondary endpoints: IR rate in cohorts B, C and D; extracranial response (ER) and overall response (OR) rates; intracranial, extracranial, and overall DCRs; duration of IR, ER, and OR; PFS; OS; and safety BID, twice daily; ECOG PS, eastern Cooperative Oncology Group performance status; PFS, progression-free survival; QD, once daily. anull hypothesis: IR rate of 35% in cohort A (based on activity of dabrafenid monotherapy in the BRAK-MB trial; Long GV, et al. Lancet Oncol. 212; 13: ). Investigator-assessed efficacy was confirmed by a blinded independente review committee (BIRC). Data cutoff date: November 28, 216. Final analysis (planned)

8 Intracranial Response Cohort A (n = 76) Intracranial ORR: 58% Intracranial DCR: 78% Cohort C (n = 16) Intracranial ORR: 44% Intracranial DCR: 75% Cohort B (n = 16) Intracranial ORR: 56% Intracranial DCR: 88% Cohort D (n = 17) Intracranial ORR: 59% Intracranial DCR: 82%

9 Conclusões ibraf + Inibidores do MEK (imek) são superiores aos ibraf sozinhos em termos de SG Atividade no SNC é similar a resposta sistêmica mas com menor durabilidade

10 COMBI-d: LDH Elevado Sobrevida Global (SG) Sobrevida Livre de Progressão (SLP) 1, 1, Dabrafenibe + Trametinibe (n = 76) Dabrafenibe + Trametinibe (n = 76),8,8,6,6,4,4 2-y SG, 27% 2-y SLP, 17%,2 2-y SLP, 8%, Dabrafenibe + Placebo (n = 71) y SLP, 4% 3 Meses desde a randomização Nº paciente sob risco D+T D+Pbo71 2, y SG, 17%,2 3-y SLP, 13% 3-y SG, 25% Dabrafenibe + Placebo (n = 71) +: censurado y SG, 14% Meses desde a randomização Nº paciente sob risco D+T 76 D+Pbo Flaherty et al. J Clin Oncol 33:abstr 12, 215

11 COMBI-d: LDH Normal SLP SG 1, 1, Dabrafenibe + Trametinibe (n = 133) Dabrafenibe + Trametinibe (n = 133),8,8,6 3-y SG, 54%,6 2-y SLP, 37% 3-yr SLP, 27% 2-y SLP, 21%,4,2, 2-y SG, 65% Dabrafenibe + Placebo (n = 14) +: censurado Meses desde a randomização Nº paciente sob risco D+T 9 55 D+Pbo 14,2, 36 2-y SG, 55% 3-y SG, 41% 3-yr SLP, 17% Dabrafenibe + Placebo (n = 14), Meses desde a randomização Nº paciente sob risco D+T D+Pbo Flaherty et al. J Clin Oncol 33:abstr 12, 215

12 COMBI-d: LDHa Normal e < 3 Sítios de Doença b SLP 1, 1, Dabrafenibe + Trametinibe (n = 76),8,8,6,6 Dabrafenibe + Trametinibe (n = 76) 2-y SG, 68 % 3-y SLP, 38%,4 3-y SG, 62% 2-y SG, 61%,4 3-y SG, 45%,2,2, SG Dabrafenibe + Placebo (n = 96) y SLP, 15%, 3 Meses desde a randomização Nº paciente sob risco D+T D+Pbo Dabrafenibe + Placebo (n = 96) Nº paciente sob risco D+T D+Pbo Meses desde a randomização a LDH no início do tratamento limite de normalidade; b Qualquer orgão no início do estudo com 1 metástase poderia ser considerado como um sítio único de doença; +, censurado. Flaherty et al. J Clin Oncol 33:abstr 12, 215

13 Conclusão ibraf + imek podem resultar em sobrevida a longo prazo, especialmente em pacientes com baixa carga tumoral

14 O que há de novo em inibidores de checkpoint?

15 Efficacy of Nivolumab Plus Ipilimumab Combination in Patients With Advanced Melanoma and Elevated Serum Lactate Dehydrogenase: a Pooled Analysis James Larkin,1 Pier Francesco Ferrucci,2 Rene Gonzalez,3 Luc Thomas,4 Michele Maio,5 Andrew Hill,6 Michael Postow,7 Kerry J. Savage,8 Jessica C. Hassel,9 Pippa Corrie,1 John Wagstaff,11 Laurent Mortier,12 Dirk Schadendorf,13 Omid Hamid,14 Georgina V. Long,15 Ivan Marquez-Rodas,16 Piotr Rutkowski,17 Dana Walker,18 Rafia Bhore,18 Vanna Chiarion-Sileni,19,* David Hogg2,* 1Royal Marsden Hospital, London, UK; 2European Institute of Oncology, Milan, Italy; 3University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 4Department of Dermatology, Centre Hospitalier Lyon Sud, Pierre-Bénite Cedex, France; 5University Hospital of Siena, Siena, Italy; 6Tasman Oncology Research, QLD, Australia; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA; 8BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; 9Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany; 1Addenbrooke s Hospital, Cambridge, UK; 11South West Wales Cancer Institute and Swansea University College of Medicine, Swansea, UK; 12Université de Lille, INSERM U1189, CHRU, Lille, France; 13Department of Dermatology, University of Essen, Essen, Germany; 14The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 15Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; 16Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 17Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 18Bristol-Myers Squibb, Princeton, NJ, USA; 19Oncology Institute of Veneto IRCCS, Padua, Italy; 2Princess Margaret Cancer Centre, Toronto, ON, Canada. *Contributed equally to this study

16 Best Response to Treatment 1 NIVO+IPI 9 8 NIVO IPI 65% ORR,a % (95% CI) 7 51% 6 45% 33% 5 31% 4 23% 17% 3 1% 2 1 n LDH ULN aby RECIST v LDH > ULN LDH > 2x ULN

17 Progression-Free Survival LDH ULN LDH > ULN Median PFS, months (95% CI) 8 71% NIVO + IPI NIVO IPI (n = 269) (n = 316) (n = 23) NR (11.7, NR) (7.7, 2.2) (3.1, 5.1).7.4 (.6,.9) (.3,.5) HR (95% CI) NIVO+IPI over 7 NIVO or IPI 56% 6 9 Median PFS, months (95% CI) 8 HR (95% CI) PFS (%) PFS (%) 5% 47% 35% 4 3 (n = 126) (2.9, 9.6) (2.6, 3.2) (2.6, 2.8) NIVO or IPI.8.5 (.6, 1.) (.4,.6) 47% 5 38% 17% 35% 4 34% 3 23% 2 IPI (n = 191) 6 54% 6% 5 NIVO (n = 138) NIVO+IPI over 7 NIVO+IPI 29% 28% % 1 7% 6% Time (Months) Time (Months) Number of Patients at Risk Number of Patients at Risk NIVO+IPI NIVO+IPI NIVO NIVO IPI NIVO+IPI CI = confidence interval; HR = hazard ratio; NR = not reached. IPI NIVO 126 IPI

18 PFS in Patients With LDH > 2x ULN 1 NIVO+IPI NIVO+IPI NIVO IPI Median PFS, months (95% CI) (n = 43) NIVO (n = 58) IPI (n = 31) 2.6 (1.7, 2.9) 2.1 (1.9, 2.6) 2.3 (1.7, 2.6).7 (.5, 1.1).5 (.3,.9) HR (95% CI) NIVO+IPI over NIVO or IPI PFS (%) % 3 2 2% 17% 1% 1% 18% Time (Months) Number of Patients at Risk NIVO+IPI NIVO IPI 31 2

19 KEYNOTE-6: Impact of Baseline Serum Lactate Dehydrogenase Concentration on Efficacy in the Study of Pembrolizumab vs Ipilimumab Blank C,1 Ribas A,2 Long GV,3 Mortier L,4 Carlino MS,5 Lotem M,6 Lorigan P,7 Neyns B,8 Petrella TM,9 Puzanov I,1 Richtig E,11 O Day SJ,12 Masucci G,13 Lebbe C,14 Steven N,15 Lutzky J,16 Hille D,17 Ebbinghaus S,17 Ibrahim N,17 McNeil C 18 1Netherlands Cancer Institute, Amsterdam, Netherlands; 2University of California, Los Angeles, Los Angeles, CA, USA; 3Melanoma Institute Australia, the University of Sydney, Mater Hospital, and Royal North Shore Hospital, Sydney, NSW, Australia; 4Université Lille, Centre Hospitalier Régional Universitaire de Lille, Lille, France; 5Westmead and Blacktown Hospitals, Melanoma Institute Australia, and the University of Sydney, Sydney, NSW, Australia; 6Sharett Institute of Oncology, Hadassah Hebrew Medical Center, Jerusalem, Israel; 7University of Manchester and the Christie NHS Foundation Trust, Manchester, UK; 8Universitair Ziekenhuis Brussel, Brussels, Belgium; 9Sunnybrook Health Sciences Center, Toronto, ON, Canada; 1Roswell Park Cancer Institute, Buffalo, NY, USA; 11Medical University of Graz, Graz, Austria; 12The John Wayne Cancer Institute at Providence St. John s Health Center, Santa Monica, CA, USA; 13Karolinska Institute, Stockholm, Sweden; 14APHP Dermatology CIC University Paris 7, Hôpital Saint-Louis, Paris, France; 15Queen Elizabeth Hospital, Birmingham, UK; 16Mount Sinai Medical Center, Miami, FL, USA; 17Merck & Co., Inc., Kenilworth, NJ, USA; 18Chris O Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, NSW, Australia

20 Objective Response Rate RECIST v1.1 by Central Review in Patients With Baseline LDH 1 ULN, >1 to 2 ULN, and > 2 ULN Blank et al, KN6, SMR, 216

21 PFS RECIST v1.1 by Central Review Patients with LDH 1 ULN, >1 to 2 ULN, and > 2 ULN Blank et al, KN6, SMR, 216

22 Conclusão Pacientes com carga tumoral mais baixa, representado por DHL normal, tem maior chance de sobrevida de longo prazo

23 Inibinidores de Checkpoint em Metástases Cerebrais

24 Fase II aberto, não randomizado N = 36 (18 melanomas/18 NSCLC PDL1+) 1 metástase SNC não tratada ou PD em SNC (5-2 mm) Pembrolizumabe 1 mg/kg a cada 2 semanas Lancet Oncol 216, Epub ahead of print

25 Maximum tumour response from baseline (%) Conclusão Patients with melanoma Patients with NSCLC *Partial response Complete response Respostas: 4/18 melanomas 6/18 NSCLC -5-1 * * * * * * Lancet Oncol 216, Epub ahead of print

26 A Randomized Phase 2 Study of Nivolumab or Nivolumab plus Ipilimumab in patients with Melanoma Brain Metastases: The Anti-PD1 Brain Collaboration (ABC) Georgina V. Long, Victoria Atkinson, Alexander M. Menzies, Alexander David Guminski, Shahneen Kaur Sandhu, Michael Paul Brown, Tracy Liaw, Maria Gonzalez, Jill Davison, Elizabeth J. Paton, Richard A Scolyer, Louise Emmett, Grant A. McArthur

27 Study Design A Melanoma Brain Metastases 5mm & 4mm No previous Anti-CTLA-4 Anti-PD-1 or PD-L1 agents Previous BRAFi + MEKi allowed ECOG PS -2 R 1:1 up to n=53 No serious autoimune disease No corticosteroids (Cohort C < 1mg prednisone allowed) Total 76 Patients Recruited No prior local brain Rx & asymptomatic N = 33 Rx = Nivolumab + Ipilimumab Study Design B No prior local brain Rx & asymptomatic N = 27 Rx = Nivolumab C Previously treated or symptomatic or leptomeningeal, with MRI progression n = 16 Rx = Nivolumab

28 Best Intracranial RECIST Response Intracranial Response, n (%) CR PR SD PD NE* A: Ipi+Nivo N = 26 B: Nivo N = 25 C: Nivo N = (42%) 4 (15%) 7 (27%) 2 (8%) 12 (46%) 1 (4%) 5 (2%) 3 (12%) 2 (8%) 1 (4%) 18 (72%) 1 (4%) 1 (6%) 1 (6%) 4 (25%) 11 (69%) Best Intracranial RECIST Response Median duration of intracranial response not reached in any arm NE = Not Evaluable *Pets who deceased prior to wk 12 = PD Leptomeningeal, previous local treatment or symptoms

29 Best Intracranial RECIST Response: Drug Treatment-naïve Patients Intracranial Response, n (%) CR PR SD PD NE* A: Ipi+Nivo N = 2 B: Nivo N = 19 C: Nivo N=4 1 (5%) 3 (15%) 7 (35%) 2 (1%) 7 (35%) 1 (5%) 4 (21%) 2 (11%) 2 (11%) 1 (5%) 13 (68%) 1 (5%) 1 (25%) 1 (25%) 1 (25%) 2 (5%) Best Intracranial RECIST Best Intracranial Response:RECIST <br />Drug Response Treatment-naïve Patients Median duration of intracranial response not reached in any arm NE = Not Evaluable *Pets who deceased prior to wk 12 = PD Leptomeningeal, previous local treatment or symptoms

30 Change from Baseline (%) Intracranial Response All Patients Cohort A: IC RR = 42% Cohort B: IC RR = 2% 2 15 BRAFi+MEKi Pretreated Cohort A: RR = 16% Cohort B: RR = 16% Intracranial Response ****** ****** Cohort A: Nivo+Ipi Cohort B: Nivo alone ** **

31 Intracranial Progression-Free Survival: Intracranial Best response All Patients (Cohorts A+B+C) Intracranial Progression-Free Survival:<br />Intracranial Best Response All Patients (Cohorts A+B+C)

32 Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with melanoma Metastatic to the Brain: results of the Phase II Study CheckMate 24 Hussein Abdul-Hassan Tawbi, Peter A. J. Forsyth, Alain Patrick Algazi, Omid Hamid, F. Stephen Hodi, Stergios J. Moschos, Nikhil I. Khushalani, Rene Gonzalez, Christopher D. Lao, Michael Andrew Postow, Michael B. Atkins, Marc S. Ernstoff, Igor Puzanov, Ragini Reiney Kudchadkar, Reena Parada Thomas, Ahmad A. Tarhini, Joel Jiang, Alexandre Avila, Sheena Demelo, Kim Allyson Margolin

33 Response to Treatment All patients (N = 75) Global Intracranial Extracranial 4 (5) 36 (48) 4 (5) 18 (24) 13 (17) 16 (21) 25 (33) 4 (5) 18 (24) 12 (16) 5 (7) 32 (43) 2 (3) 16 (21) 2 (27) Objective response rate, % (95% CI) 53 (41 65) 55 (43-66) 49 (38 61) Clinical benefit ratec, % (95% CI) 59 (47 7) 6 (48 71) 52 (4-64 Best overall response, n (%) Complete response Partial response Stable disease Progressive diaseasea Not evaluable b aconfirmed and unconfirmed progressive disease bincludes unconfirmed responses cclinical benefit rate = complete response + partial response + stable disease 6 months

34 PFS PFS

35 Conclusão Ipi + Nivo tem alto grau de atividade antitumoral em SNC, da ordem de 5% de resposta objetiva e a sobrevida pode ser duradoura AntiPD1 isolado tem atividade mais modesta, da ordem de 2%

36 Algoritmo de Tratamento

37 Pacientes com baixa carga tumoral e sem envolvimento do SNC MUTADO AntiPD1 se PD BRAF Status ibraf + imek Não há opção padrão: SELVAGEM Considerar Ipi QT RT + AntiPD1 HD IL-2

38 Pacientes com baixa carga tumoral e comprometimento limitado do SNC Radiocirurgia estereotáxica* + AntiPD1 ou AntiPD1 isolado ou Ipi + AntiPD1** MUTADO se PD BRAF Status ibraf + imek Sem terapia padrão: SELVAGEM Considerar Ipi QT RT + AntiPD1 HD IL-2 *Ressecção deve ser considerada para lesões não passíveis de radiocirurgia estereotáxica ou que exigem corticosteroides **Ipi+antiPD1 representa também um solida opção, se disponível

39 Pacientes com alta carga tumoral e sem envolvimento do SNC MUTADO ibraf + imek SELVAGEM Ipi + AntiPD1 BRAF Status Mínima PD

40 Pacientes com alta carga tumoral e envolvimento extensivo do SNC MUTADO BRAF Status SELVAGEM COM esteróide ibraf + imek SEM esteróide* Ipi + AntiPD1* COM esteróide Opções limitadas WBI + QT QT isolada Mínima PD *Considerar bevacizumabe para descontinuar ou reduzir corticosteroides. Pacientes deve estar com 1mg ou menos de prednisona ou equivalente para imunoterapia.

41 Thank you