Moving forward in Early Therapy: Redefining Treatment for Adjuvant Melanoma & Checkmate 238  Eva Muñoz Couselo, MD, PhD Oncología médica Hospital Vall d’Hebrón, Barcelona Contiene información e imágenes con permiso para su utilización como fuente 1506LA1901857-01

TNM Staging Gershenwald JE et al. CA Cancer J Clin 2017.

Stage III Survival AJCC 8th AJCC 7th Balch CM et al. J Clin Oncol 2009. Gershenwald JE et al. CA Cancer J Clin 2017.

Benefit of Adjuvant Treatment Michielin O. ASCO 2018.

Meta-analysis of adjuvant IFN-α 15 Trials 7699 patients Event-free Survival Overall Survival Ives NJ et al. Eur J Cancer 2017.

New IO Therapeutic Options in Advanced Disease 09/04/14: Pembrolizumab approved for unresectable or metastatic melanoma after lpilimumab or a BRAF inhibitor 22/12/14: Nivolumab approved for unresectable or metastatic melanoma after lpilimumab or a BRAF inhibitor 2012-Nivolumab (αPD1) displays remarkable efficacy in phase 1 clinical trial in patients with advanced melanoma, non-small cell lung cancer, and renal carcinoma. 03/04/2017: Avelumab approved for Merckel cell carcinoma 24/07/2017: Ipilimumab approved by FDA for pediatric patients 12 years and older with unresectable or metastatic melanoma. 2012 2014 2015 2016 2010 2011 2012 2013 2014 2015 2016 2017-2018 30/09/15: Ipilimumab+nivolumab approved for BRAF V600 wild-type unresectable or metastatic melanoma 27/10/15: T-VEC approved for locally recurrent malignant melanoma 28/10/15: Ipilimumab approved for adjuvant therapy of Stage 3 melanoma 24/11/15: Nivolumab approved for first line therapy of metastatic melanoma regardless of BRAF mutation status 18/12/15: Pembrolizumab approved for first line therapy of metastatic melanoma regardless of BRAF mutation status 20/12/2017: Nivolumab approved by FDA for adjuvant therapy in patients with completely resected melanoma with lymph node involvement or metastatic disease. 2010-FDA approval of sipuleucel-T targeting a specific cancer antigen was the first FDA-approved specific immunotherapy 2011-FDA approval of ipilimumab for unresectable or metastatic melanoma Fig, adapted from: “Leisha A. Emens, et al.Cancer inmonotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. EJC 81 (2017) 116-129. Adaptación de la Fig. 1. The recent accelerationand expansion of cancer inmonotherapy approvals. A timeline ilustrates regulatory approvals in the United States since 2010” 2013-CAR T cell therapy achieves 89% response rate in ALL and complete responses in B-ALL *US FDA APPROVALS

IO Overall Survival in Advanced Disease Inhibidores del punto de control para el melanoma metastásico: ensayos de fase 3 que evalúan el tratamiento de primera línea Mediana SLP (meses) IPI CheckMate 0664 (3 mg/kg, BRAF WT) 5.14 73%4 NIVO CheckMate 0676 (3 mg/kg) 6.96 74%7 KEYNOTE 00610 (10 mg/kg) Dosis no aprobada Q2W Q3W 5.611 4.111 74%10 68%10 PEMBRO NIVO+IPI CA184-0241 (IPI 10 mg/kg + DTIC) CheckMate 0676 (IPI 3 mg/kg + NIVO 1 mg/kg) 2.82 11.56 1-año OS 47%1 73%7 OS largo plazo 5 años (18%)3 2 años (58%)5 2 años (59%)7 2 años (55%)11 2 años (64%)7 Phase 1 (NIVO) CheckMate 003 OS 5 años 35% (3 mg/kg)14 3 años (52%)8 33 años (50%)12 3 años (58%)8 Phase 1 (PEMBRO) KEYNOTE 001 OS 5 años 34% todos los pts (41% en pts tto-naive )15 4 años (46%)9 4 años 42%; 44% en tx-naive)13 4 años (53%)9 Datos independientes, ensayos clinicos no comparativos por lo que no se busca una comparación indirecta de los mismos DTIC = dacarbazine; IPI = ipilimumab; OS = overall survival; NIVO = nivolumab; PEMBRO = pembrolizumab; PFS = progression-free survival; pts = patients; Q2W = every 2 weeks; Q3W = every 3 weeks; tx = treatment; WT = wild type. 1. Robert C et al. N Engl J Med. 2011;364:2517-2526. 2. Wolchok J et al. Presented at ASCO 2011; abstract LBA5. 3. Maio M et al. J Clin Oncol. 2015;33:1191-1196. 4. Robert C et al. N Engl J Med. 2015;372:320-323. 5. Atkinson V et al. Presented at SMR 2015. 6. Larkin J et al. N Engl J Med. 2015;373:23-34. 7. Larkin J et al. Presented at AACR 2017; abstract CT075. 8. Wolchok et al. N Engl J Med. 2017;377:1345-1356. 9. Hodi FS et al. Presented at ESMO 2018; abstract LBA44. 10. Robert C et al. N Engl J Med. 2015;372:2521-2532. 11. Schachter J et al. Lancet. 2017;390:1853-1862. 12. Robert C et al. ASCO 2017; abstract 9504. 13. Long GV et al. Presented at ASCO 2018; abstract 9503. 14. Hodi FS et al. Presented at AACR 2016; abstract CT00. 15. Hamid O et al. Presented at ASCO 2018; abstract 9516. Previous adjuvant treatment

R- EVOLUTION ¿Necesidad de cirugía y biopsia SLN? Evaluación de respuesta Discordancia radiológica y resultados patológicos. Definición de criterios de PCR. Pérdida de factores pronósticos estándar: número LMN, volumen del tumor, etc. Enfermedad refractaria primaria. Selección de pacientes: estadios II / IIIa Selección y duración del tratamiento : qué tratamiento y ¿por cuanto tiempo? Perfiles de respuesta - tratamiento secuencial. Cómo manejar la recaída. BRAF mutados. El 50% de los pacientes todavía mueren de su enfermedad. Opciones limitadas para pacientes BRAF wt BRAF mutados Secuenciación óptima y combinaciones. ¿Biomarcadores?

Factors for Consideration in Adjuvant Treatment Decisions Data Risk-benefit Thickness Disease stage/risk of recurrence Patient wishes Ulceration The decision about whether and how to treat in the adjuvant setting should take into account a variety of factors. These factors should be carefully considered and discussed with the patient1 Factors for consideration include The likely risk of a patient’s disease recurring and the parameters that predict for recurrence (melanoma thickness, presence of ulceration, and regional and distant metastatic burden)2 The risk-benefit of potential treatments1 The availability of treatments for advanced disease that have been demonstrated to improve OS2 The patient’s wishes1 References Garbe C, Peris K, Hauschild A, et al; European Dermatology Forum (EDF); European Association of Dermato-Oncology (EADO); European Organisation for Research and Treatment of Cancer (EORTC). Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline—update 2016. Eur J Cancer. 2016;63:201-217. Davar D, Kirkwood JM. Adjuvant therapy of melanoma. Cancer Treat Res. 2016;167:181-208. Garbe 2016/p208/c2/para 2 Type/no. of positive +LNs Options for advanced disease Davar 2017/p183-4 Garbe 2016/p208/c2/para 2 Davar 2017/p204/para 3 Garbe 2016/p208/c2/para 2

TODOS LOS PACIENTES CON BSGC + -> LINFADENECTOMIA

Ipilimumab Eggermont A et al. ESMO 2016.

Ipilimumab

Nivolumab

Nivolumab Weber J et al. ESMO 2017 Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Nivolumab Weber J et al. ESMO 2017. Weber J et al. NEJM 2017. Weber J et al. ASCO 2018

Pembrolizumab KEYNOTE-054 Eggermont A et al. AACR 2018.

Pembrolizumab Eggermont A et al AACR 2018

Adjuvant melanoma landscape

Adjuvant melanoma landscape Checkmate 238 trial Adjuvant melanoma landscape Weber J et al. N Engl J Med 2017; 377:1824-1835, Eggermont A et al. N. Engl J Med 2018; http://bit.ly/2FfY3ZY

Conclusions Fin de la era del tratamiento con Interferón y con Ipilimumab en el contexto adyuvante. La linfadenectomía no debería ser un estándar para todos los pacientes N+. Los tratamientos activos en el melanoma en estadio IV presentan una traducción directa de su eficacia en el contexto adyuvante. Nivolumab durante 1 año de tratamiento, ha demostrado una reducción estadísticamente significativa del riesgo de recidiva en pacientes N+ BRAF wt y mutados en estadios III y en estadio IV resecado, con un perfil de efectos adversos favorable y manejable. Existe una gran necesidad de biomarcadores que ayuden a identificar aquellos pacientes de alto riesgo que realmente precisen tratamientos complementarios.

emunoz@vhio.net