SIMPOSIO EDUCACIONAL MELANOMA CUÁL ES EL PAPEL ACTUAL DE LA QUIMIOTERAPIA? Luis de la Cruz Merino Sº Oncología Médica HUVMacarena (Sevilla)

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1 SIMPOSIO EDUCACIONAL MELANOMA CUÁL ES EL PAPEL ACTUAL DE LA QUIMIOTERAPIA? Luis de la Cruz Merino Sº Oncología Médica HUVMacarena (Sevilla)

2 Melanoma: Enfermedad Avanzada INTRODUCCIÓN TRATAMIENTO SISTÉMICO CLÁSICO MONOTERAPIA POLIQUIMIOTERAPIA INMUNOQUIMIOTERAPIA ABRAXANE CONSIDERACIONES FINALES

3 INTRODUCCIÓN -Incidencia y mortalidad anuales en Europa: / Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in Ann Oncol 2007; 18: Incidencia esperada en población 1/68 -Supervivencia media melanoma avanzado 6-9 meses -Sólo 5% de largos supervivientes Tradicionalmente considerado poco quimiosensible Potencial antigénico/inmunogénico: regresiones espontáneas, asociación fenómenos autoinmunes-mejor pronóstico, TIL, neoantígenos (melana/mart-1, tirosinasa, gp-100,etc)

4 MMM según última edición TNM

5 TRATAMIENTO SISTÉMICO CLÁSICO

6 Tratamiento sistémico Tasas de respuesta < 20% DTIC, Temozolamida, Nitrosoureas (Fotemustina) Cisplatino y otras Subgrupos con mejor pronóstico: metástasis cutáneas, PB,etc DTIC sigue siendo el estándar a comparar: TRO 15-25% TRC < 5% MDR 5-6 meses Inmunomoduladores: IL-2 e IFN α-2b, TRO 10-20% Mejores resultados IL-2 a altas dosis en bolo: 7% largos supervivientes (Atkins Cancer J Sci Am 2000)

7 VARIOS AGENTES, ACTIVIDAD MODESTA

8 Tratamiento sistémico Middleton et al JCO pax TMZ vs DTIC *SV mediana 7.7 vs 6.4 meses (P 0.054) SLP 1.9 vs 1.5 meses(p.012) TMZ mejor tolerado y beneficio QoL (QLQ C-30 EORTC) ENSAYO NEGATIVO Avril et al JCO pax FTM vs DTIC *TRO 15,2% vs 6.8% (p.043) SV mediana 7.3 vs 5.6 meses (P 0,067) Mayor toxicidad hematológica grupo Fotemustina (G 3-4) No diferencias QoL ENSAYO POSITIVO

9 Tratamiento sistémico - 80 combinaciones. Legha-CVD, Dartmouth-CBDT - Estudios fase II resultados favorables Metanálisis Cancer TMX no aporta beneficio en TRO y SG Los esquemas de combinación TRO sin impacto en SG

10 Tratamiento sistémico Metaanálisis Melanoma Research 2001 Huncharek 3273 pax de 20 estudios Combinaciones presentan un 23% TRO sin impacto SG

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13 2010: NINGÚN TRATAMIENTO INCREMENTO SG RESPECTO A DTIC

14 a partir de RESPUESTA INMUNE RUTA MAP-KINASAS

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18 Hodi 2010

19 Hodi 2010

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21 NUEVOS QT ABRAXANE

22 Phase 3 Study of nab -Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma ABRAXANE Evan M. Hersh,1 Michele Del Vecchio,2 Michael P. Brown,3 Richard Kefford,4 Carmen Loquai,5 Alessandro Testori,6 Shailender Bhatia,7 Ralf Gutzmer,8 Andrew Haydon,9 Caroline Robert,10 Alicia Clawson,11 Ileana Elias,11 Markus F Renschler,11 Axel Hauschild12 1 Arizona Cancer Center, Tucson, AZ, USA ; 2 Istituto Nazionale Tumori, Milano, Italy; 3 Royal Adelaide Hospital, Australia; 4 Westmead Hospital and Melanoma Institude, Australia; 5 Universitätsmedizin Mainz, Germany; 6 Istituto Europeo di Oncologia, Milano, Italy; 7 Seattle Cancer Care Alliance, USA; 8 Medizinische Hochschule Hannover, Germany; 9 Alfred Hospital, Melbourne, Australia; 10 IGR Centre de Lutte Contre le Canc, Villejuif, France; 11 Celgene, Summit, NJ, USA; 12 Universitätsklinkum Schleswig-Holstein, Kiel, Germany Hersh, et al. Phase 3 Study of nab -Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.

23 nab-paclitaxel: Phase I and II Studies No premedication; No special tubing; No acute toxicities typical of taxanes While cremophor-paclitaxel [1,2] or docosahexaenoic acid-paclitaxel [3] produced limited clinical benefit, nab-paclitaxel produced promising efficacy: nab-paclitaxel, 30-min IV infusion, weekly 3 of 4 weeks Phase 1, Advanced Solid Tumors [4] mg/m2 weekly (14 Melanoma pts) N = 39 DCR, % 38 The 150 mg/m2 dose level was well tolerated in lightly pretreated patients Phase 2, Metastatic Melanoma [5] 150 mg/m2 Chemo-naïve N = 37 PR, % DCR, % PFS, median month OS, median month Walker, Melanoma Res, Pfugfelder, Plos Once, Bedikian, Ann Oncol, Nyman, JCO, Hersh, Cancer DCR, disease control rate; OS, overall survival; PFS, progression-free survival; PR, partial response Hersh, et al. Phase 3 Study of nab -Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.

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27 BRIM 3 Median OS for vemurafenib confirmed to be better than for DTIC

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30 Preferred Term Patients with at least 1 TRAE, % Patients with at least 1 serious TRAE, % Hematologic Adverse events, %* Neutropenia Leukopenia Lymphocytopenia Thrombocytopenia Anemia Nonhematologic Adverse Events, %* Peripheral Neuropathy** Fatigue Alopecia Neuropathy, median days Time to Onset Time to Improvement by 1 grade nab-paclitaxel (n = 257) Dacarbazine (n = 258) * Except for lymphocytopenia, all events P < 0.05 ** All but 2 neuropathy cases were grade 3 Hersh, et al. Phase 3 Study of nab -Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.

31 31 CA033 A Phase III Trial of nab-paclitaxel vs Dacarbazine in Chemotherapy-Naive Patients With Metastatic Melanoma: A Subanalysis Based on BRAF Status EM Hersh, M Del Vecchio, MP Brown, R Kefford, C Loquai, A Testori, C Robert, M Li, I Elias, MF Renschler, A Hauschild Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

32 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Study Design (Cont) Endpoints Primary efficacy endpoint: PFS per blinded radiology assessment, RECIST v1.0 Other endpoints: OS, ORR, DCR, and safety/tolerability using NCI CTCAE v3 Methods Protocol modified in 2011 to collect BRAF mutational status and analysis plan amended prior to data lock to include PFS and OS by BRAF status DCR, disease control rate; HR, hazard ratio; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Criteria In Solid Tumors. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society or Clinical Oncology 2013; May 31-June 4; Chicago, IL.

33 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Objective of the Subanalysis 33 To evaluate the efficacy and safety of nab-paclitaxel vs dacarbazine by BRAF mutation status Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

34 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics 34 BRAF Status Wild Type Mutant Unknown nab-p DTIC nab-p DTIC nab-p DTIC Patient Characteristics n = 116 n = 108 n = 65 n = 67 n = 83 n = 90 Median years Age (range) (21-85) (38-86) (25-82) (30-87) (32-85) (28-83) Sex, % Male Region, % ECOG PS, % North America Western Europe Australia DTIC, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; nab-p, nab-paclitaxel; ULN, upper limit of normal. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

35 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics (Cont) 35 BRAF Status Wild Type Mutant Unknown Patient Characteristics Metastatic stage, % LDH category, % Prior therapy for metastatic disease, % M1a M1b M1c < 0.8 ULN ULN > ULN nab-p n = DTIC n = nab-p n = DTIC n = nab-p n = DTIC n = Yes DTIC, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; nab-p, nab-paclitaxel; ULN, upper limit of normal. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

36 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Results: Independent Assessment of PFS by BRAF Status 36 DTIC, dacarbazine; mo, months; nab-p, nab-paclitaxel; PFS, progression-free survival. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

37 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Results: Interim OS by BRAF Status 37 DTIC, dacarbazine; mo, months; nab-p, nab-paclitaxel; OS, overall survival. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

38 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Results: Poststudy Anticancer Therapy by BRAF status 38 BRAF Status Wild Type Mutant Unknown Anticancer Therapy nab-p n = 116 DTIC n = 108 nab-p n = 65 DTIC n = 67 nab-p n = 83 DTIC n = 90 Poststudy therapy, % BRAF inhibitor Ipilimumab < Among patients with a BRAF mutation, the treatment effect in favor of nab-p vs DTIC on interim OS remained after adjustment for subsequent ipilimumab and/or BRAF inhibitor therapy Adjusted median OS (ipilimumab and BRAF inhibitor): 12.2 vs 8.8 months (HR 0.633; P = 0.067) Adjusted median OS (BRAF inhibitor): 12.0 vs 8.4 months (HR 0.838; P = 0.463) DTIC, dacarbazine; HR, hazard ratio; nab-p, nab-paclitaxel; OS, overall survival. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

39 CA033 (Hersh): Phase III Trial of nab-p vs DTIC in Chemotherapy-Naive Metastatic Melanoma Authors Conclusions 39 The treatment effect (PFS and interim OS) was independent of BRAF mutation status, benefiting all patients who received nabpaclitaxel vs dacarbazine Interim OS of 16.9 months in patients with a BRAF mutation is promising AEs were manageable; grade 3 peripheral neuropathy occurred with nab-paclitaxel treatment, but symptoms improved within 2 to 3 months and 40% of patients were able to resume treatment nab-paclitaxel should be considered as a new standard chemotherapy option in chemotherapy-naive patients with metastatic melanoma irrespective of BRAF mutation status AE, adverse event; OS, overall survival; PFS, progression-free survival. Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology 2013; May 31-June 4; Chicago, IL.

40 EFECTO VACUNA

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42 I P I L I M U M A B TEMOZOLAMIDA 1 FOTEMUSTINA 2 ABRAXANE??? DACARBACINA 3 TRO 30% SLP a 6 meses 45% SG 1 año 68% TRO 29% TRO 40% M1 cerebrales Mediana SG 13,3 meses Fase 2 random (+/- DTIC) TRO 5,4 vs 14,3% SG a 3 años 9 vs 20% Patel Di Giacomo Hersh

43 CONCLUSIONES MM tradicionalmente considerado poco quimiosensible A pesar de agentes antidiana e inmuno, una mayoría de pax con MM recibirá QT en algún momento PoliQT y bioqt incrementa TRO pero no impacto SG 2 estudios randomizados positivos de monoqt frente a DTIC: fotemustina y nab-paclitaxel Nab-paclitaxel nueva alternativa terapéutica en MM, mejora SLP (en espera de datos maduros de SG) Estrategias de combinación QT+ inmuno pueden potenciar efectos (sinergia)