MELANOMA MESA REDONDA 4 DEFINIENDO LA SECUENCIA ÓPTIMA DE TRATAMIENTO EN CÁNCER AVANZADO

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1 MESA REDONDA 4 DEFINIENDO LA SECUENCIA ÓPTIMA DE TRATAMIENTO EN CÁNCER AVANZADO MELANOMA Salvador Martín Algarra Clínica Universidad de Navarra Pamplona

2 En los últimos años ha habido considerables avances en el conocimiento de la biología molecular del melanomay de los mecanismo de la respuesta inmune, que han permitido identificar nuevos agentes que están cambiado los algoritmos terapéuticos en esta enfermedad.

3 Avances en terapias dirigidas e inmunoterapia de melanoma Actitud más proactiva a referir pacientes con melanoma avanzado a Oncología Médica. Estácambiado el perfil de pacientes.

4 Avances en terapias dirigidas e inmunoterapia de melanoma Aumento en el número de Ensayos Clínicos para Melanoma. Informacion y experiencia extrapolable a otras neoplasias.

5 Nuevos Agentes Activos en Melanoma avanzado Ipilimumab Vemurafenib Trametinib Dabrafenib Pembrolizumab Nivolumab + Cobimetinib + Trametinib Radiocirugía RT Modulada Cirugía DTIC, Fotemustina, Temozolamida, Paclitaxel, Carboplatin, Bevacizumab IL-2, IF ILP Imatinib Nab-Paclitaxel

6 Agentes Activos en Melanoma avanzado Ipilimumab en 1ª y 2ªlínea Vemurafenib + Cobimetinib (UC) Trametinib Dabrafenib + Trametinib (UC) Pembrolizumab UC tras Pr a Ipilimumab Nivolumab UC tras Pr a Ipilimumab DTIC, Fotemustina, Temozolamida, Paclitaxel, Carboplatin, Bevacizumab IL-2, IF ILP Imatinib Nab-Paclitaxel

7 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Documentos de Consenso

8 Marquez I. et al

9 ESMO&EDF/EADO/EORTCSeptember 2012 ESMO Ann Oncol (R Dummer et al) EDF, EADO y EORTC Eur J Cancer (C Garbe et al)

10 Both publications agree that... Current data are not mature and an definite algorithms for MM cannot be established. Therapeutic decisions in stage IV melanoma must be taken with a multidisciplinary perspective. This area is changing quickly. More data is needed to define the optimal sequence.

11 Garbe et al La dosis aprobada de Ipilimumab es de 3 mg/kg en pacientes con melanoma avanzado previamente tratados

12 Searching for the Algorithm Mutation testingof tumour tissue (at least BRAF; CKIT in subtypes) is a prerequisite for treatment decisions. BRAF mutated patients should be offered treatment with BRAF inhibitors or experimental drugs blocking the MAP kinase and PI3K pathways, preferably still in the context of clinical trials designed to reduce the emergence of drug resistance.

13 Searching for the Algorithm Patients whose disease progresses on first-line treatment and with health status of presumably six or more months should be offered ipilimumabor other immunotherapies in the context of clinical trials as they are made available. BRAFwtpatients and those progressive under BRAFi and immunotherapies should be considered for Chemotherapy. c-kit inhibitors may have a role in the small proportion of ckit mutant melanomas

14 Aspects to consider: It may be necessaryor even desirabletodeviatefromtheseguidelines in theinterestofspecificpatientsorunderspecialcircumstan ces.

15 Aspects to consider in Immunotherapy PatientswithstablediseaseorinitialdiseaseprogressionafterIpilimumab may benefitwithprolongedsurvival. Unfortunately, no predictivebiomarkers are so far available. PD-1 antibodiesshowed in a largephase II trialhighefficacywithan ORR of 28% and a PFS rateof 41% after24weeks. Preliminaryevidencesuggeststhattheexpressionof PD- L1onthetumourtissue may selectforpatientswithanimproved response to PD-1 axisinhibitors.

16 Dummer et al

17 Dummer et al

18 Tratamiento en 2ª/3ª línea Tratamiento en 1ª línea Recomendado Dummer et al. Instrucciones no específicas Actualmente fuera de indicación Determine mutational status in stage IV patients NRAS mutated BRAF mutated BRAF WT Symptomatic, large tumor burden Asymptomatic, small tumor burden Inhibitor Vemurafenib Ipilimumab? Ipilimumab 1st line? Clínical Trial or Chx/Biochx? Ipilimumab Vemurafenib? 2 nd line? Ipilimumab Clínical Trial or Chx/Biochx? Ipilimumab is approved by EMA only on 2ªline

19 Conclusions Current recommendations are not definite and must be applied with judicious clinical criteria. Ipilimumab is active regardless mutational status (BRAF) and currently is approved by EMA in second line, although FDA and some guides also consider its use in first line. Future advances with immunotherapy (anti-pd1, anti PD-1L) as well as with targeted therapies (BRAF, MEK, c-kit, RAS, PI3Ki, inhibitors ) will have a great impact in future consensus documents (2015?).

20 Srivastava N, McDermott D.Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape. Cancer Manag Res Jun 20;6:

21 . Treatment algorithms in stage IV melanoma Espinosa E, GrobJJ, Dummer R, Rutkowski P, Robert C, Gogas H, Kefford R, Eggermont AM, Martin Algarra S, Hauschild A, SchadendorfD. Am J Ther Jan-Feb;22(1):61-7 A review of the recent key studies performed, followed by a discussion in an expert forum. to generate a therapeutic algorithm for stage IV melanoma.

22 . Treatment algorithms in stage IV melanoma Espinosa E, GrobJJ, Dummer R, Rutkowski P, Robert C, Gogas H, Kefford R, Eggermont AM, Martin Algarra S, Hauschild A, SchadendorfD. Am J Ther Jan-Feb;22(1):61-7 Genotyping for BRAF/ KIT should be performed before selection of therapy. Most BRAF-mutated melanoma patients and particularly those with a high tumor load,vemurafenibordabrafenibare the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role forchemotherapy either as first-line treatment in BRAF wildtype patients or as salvage therapy in second or third line Participation inclinical Trialsis strongly encouraged, either in first or in subsequent lines.

23 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA Más realista Más adecuada Más prometedora

24 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Más realista

25 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF KIT Metástasis cerebrales LDH Karnosky/ECOG Volumen tumoral Cinética deprogresión Características del Paciente/Centro Aprobacion por organismos reguladores Resultados de ensayos clinicos

26 aa SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Cirugía Metastasis única resecable (PET/TC y RM SNC). Paliación en situaciones singulares. Enfermedad residual en respuesta mantenida. ILP

27 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Radioterapia Metastasis SNC (Radiocirugía). Paliación (dolor/compresion/sangrado). Tras cirugía de metástasis (?).

28 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF+ con baja carga tumoral, ECOG/LDH normal, sin mts cerebrales Vemurafenib + Cobimetinib Dabrafenib + Trametinib Ipilimumab Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab.

29 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF+ con alta carga tumoral, ECOG/LDH elevado, con mts cerebrales Vemurafenib + Cobimetinib Dabrafenib + Trametinib Radioterapia SNC Quimioterapia (Fotemustina, Temozolamida, ) Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab. GEM Ipilimumab+Rtholocraneal

30 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF wt Ipilimumab Quimioterapia Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab.

31 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Más adecuada

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33 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Más prometedora

34 Percent alive Percent alive Percent alive Maximizing clinical benefit by combining the 2 compounds or by smart sequencing strategies Vemurafenib (N=336) Dacarbazine (N=336) Immunotherapy Targeted therapy Combination + =? Years Years Years 35

35 Proportion alive Ipilimumab improve Long Term Survival Survival Rate 1.0 Ipilimumab + gp100 N=403 (95% CI) Ipilimumab + placebo N=137 (95% CI) gp100 + placebo N=136 (95% CI) 1 year 44% (0.39,0.49) 46% (0.37,0.54) 25% (0.18,0.33) 2 year 22% (0.17,0.26) 24% (0.16,0.32) 14% (0.08,0.2) Clear increase in disease survival at 1 and 2y. Long term survivors rate doubled Years Hodi, FS, et al. N Engl J Med 2010;363: Comparison HR P-value Arms A vs C 0.68 <0.001 Arms B vs C Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C)

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38 Comparison of Major Clinical End Points for BRAF Monotherapy with Combined BRAF and MEK Inhibition. Curti BD. N Engl J Med 2014;371:

39 Survival End Points. Robert C et al. N Engl J Med 2015;372:

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41 Kaplan Meier Estimates of Progression-free and Overall Survival. Robert C et al. N Engl J Med DOI: /NEJMoa

42 Combination&Sequential Studies with Ipilimumab Ipilimumab + RT (France) Ipilimumab + Fotemustine in brain metastasis patients (Italy) Ipilimumab + IL-2 (Germany) Ipilimumab + RT in brain metastasis patients (Spain) Ipilimumab + Low dose IFN as adyuvant thx (EADO) Ipilimumab + High dose IFN en neoadyuvant (HECOG) Ipilimumab + Vemurafenib (CA )

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44 Postow MA et al. N Engl J Med 2015;372:

45 SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO Inmunoterapia de combinación (Anti-PD1+ Otros: Anti CTLA4 Anti CD137.) En portadores de mutacion BRAF V600: BRAFi+MEKi Ensayo Clínico

46 Adequate clinical and laboratory profiling & New therapeutic options = Optimize treatment strategies to achieve long-term survival