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
O que há de novo em terapia alvo?
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, 2 4 6 1 12 14 16 18 2 2 Meses desde a Randomização Nº pacientes sob risco Dabrafenibe + Trametinibe Dabrafenid apenas 8 211 212 28 25 199 19 185 174 16 142 12 9 44 41 11 11 Long et al. N Eng J Med 371:1877, 214
Dabrafenibe + Trametinibe versus Vemurafenibe OS COMBI-v Dabrafenibe + Trametinibe Pacientes (%) 1 9 8 7 6 5 4 3 2 1 Nº pacientes sob risco Dabrafenibe + Trametinibe Vermurafenibe Vemurafenibe HR,69 IC 95%,53-,89 p =,5 1 352 346 352 345 2 3 4 5 6 7 8 342 341 341 331 336 315 325 299 31 295 283 285 271 247 9 1 11 12 13 14 15 16 17 18 19 2 21 Meses 263 232 232 24 23 157 125 171 122 9 85 63 64 46 46 31 32 16 15 7 3 3 2 1 1 Robert et al. N Eng J Med 371:1877, 214
Sobrevida Global (%) Vemurafenibe + cobimetinibe versus Vemurafenibe OS cobrim 1 Vemurafenibe + cobimetinibe (N=247) 9 8 7 6 Vemurafenibe + placebo (N=248) 5 4 3 2 Hazard ratio,,65 (IC 95%,,42-1,) 1 P=,46 1 3 5 7 9 11 13 15 17 Meses Nº pacientes sob risco Vemurafenibe + Cobimetinibe Vemurafenibe + Placebo 243 245 229 227 182 166 112 11 62 53 2 21 6 2 1 Larkin et al. N Eng J Med 371:1877, 214
See the Full Publication in Lancet Oncology See the Full Publication in Lancet Oncology
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: 187-195). Investigator-assessed efficacy was confirmed by a blinded independente review committee (BIRC). Data cutoff date: November 28, 216. Final analysis (planned)
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%
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
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) 6 12 18 24 3-y SLP, 4% 3 Meses desde a randomização Nº paciente sob risco D+T 76 41 D+Pbo71 2, 42 36 2-y SG, 17%,2 3-y SLP, 13% 3-y SG, 25% Dabrafenibe + Placebo (n = 71) +: censurado 6 12 18 24 3 3-y SG, 14% 36 42 48 Meses desde a randomização Nº paciente sob risco 17 12 12 7 1 5 9 4 7 2 D+T 76 D+Pbo 71 61 42 39 27 24 15 16 11 15 1 15 7 3 1 Flaherty et al. J Clin Oncol 33:abstr 12, 215
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% 6 12 18 24 3 42 48 57 34 44 24 36 7 24 5 Dabrafenibe + Placebo (n = 14) +: censurado Meses desde a randomização Nº paciente sob risco 133 96 67 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),4 1 6 12 18 24 3 36 42 48 Meses desde a randomização Nº paciente sob risco 133 126 14 D+T D+Pbo 14 133 111 87 89 8 73 71 59 61 5 1 6 Flaherty et al. J Clin Oncol 33:abstr 12, 215
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) 6 12 18 24 3-y SLP, 15%, 3 Meses desde a randomização Nº paciente sob risco D+T 76 56 D+Pbo 96 64 39 41 34 25 28 16 25 5 36 19 3 42 Dabrafenibe + Placebo (n = 96) 6 12 18 24 3 36 42 48 Nº paciente sob risco D+T 76 72 62 D+Pbo96 93 77 52 65 46 56 41 45 35 36 4 2 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
Conclusão ibraf + imek podem resultar em sobrevida a longo prazo, especialmente em pacientes com baixa carga tumoral
O que há de novo em inibidores de checkpoint?
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
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 269 316 23 LDH ULN aby RECIST v1.1. 138 191 126 LDH > ULN 43 58 31 LDH > 2x ULN
Progression-Free Survival LDH ULN LDH > ULN 1 1 9 Median PFS, months (95% CI) 8 71% NIVO + IPI NIVO IPI (n = 269) (n = 316) (n = 23) NR (11.7, NR) 11.3 4.1 (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) 5.2 2.7 2.6 (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% 2 1 15% 1 7% 6% 3 6 9 12 15 18 21 24 27 3 3 6 9 Time (Months) 12 15 18 21 24 27 Time (Months) Number of Patients at Risk Number of Patients at Risk NIVO+IPI 269 213 172 149 131 125 16 67 28 2 NIVO+IPI 138 74 59 53 44 43 36 18 4 NIVO 316 213 173 155 133 118 15 51 1 NIVO 191 74 58 51 49 42 37 15 5 IPI 23 126 71 53 43 37 24 15 5 32 16 12 7 6 4 3 1 NIVO+IPI CI = confidence interval; HR = hazard ratio; NR = not reached. IPI NIVO 126 IPI
PFS in Patients With LDH > 2x ULN 1 NIVO+IPI NIVO+IPI NIVO IPI 9 8 7 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 (%) 6 5 4 29% 3 2 2% 17% 1% 1% 18% 1 3 6 9 12 15 18 21 24 27 Time (Months) Number of Patients at Risk NIVO+IPI 43 14 12 11 8 8 6 1 NIVO 58 13 9 5 5 5 5 4 2 IPI 31 2
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
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
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
Conclusão Pacientes com carga tumoral mais baixa, representado por DHL normal, tem maior chance de sobrevida de longo prazo
Inibinidores de Checkpoint em Metástases Cerebrais
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
Maximum tumour response from baseline (%) Conclusão 25 2 15 1 5 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
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
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
Best Intracranial RECIST Response Intracranial Response, n (%) CR PR SD PD NE* A: Ipi+Nivo N = 26 B: Nivo N = 25 C: Nivo N = 16 11 (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
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
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 1 5-5 -1 ****** ****** Cohort A: Nivo+Ipi Cohort B: Nivo alone ** **
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)
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
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
PFS PFS
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%
Algoritmo de Tratamento
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
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
Pacientes com alta carga tumoral e sem envolvimento do SNC MUTADO ibraf + imek SELVAGEM Ipi + AntiPD1 BRAF Status Mínima PD
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.
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