SITUACIÓN ACTUAL DE LA INMUNOTERAPIA EN EL MELANOMA METASTÁTICO CASO(S) CLÍNICO(S) Y ACTUALIZACIÓN

SITUACIÓN ACTUAL DE LA INMUNOTERAPIA EN EL MELANOMA METASTÁTICO CASO(S) CLÍNICO(S) Y ACTUALIZACIÓN Mª Carmen Alonso López Servicio de Oncología Médica. Hospital de Albacete

20 ENERO 2017

1º Caso clinico: paciente que va bien con inmunoterapia 71 Añós. No alergias medicamentosas. No DM. No HTA. Dislipemia (Atorvastatina). FEBRERO/2006: ADENOCA PRÓSTATA (pt2a). Prostatectomía radical laparoscópica. Revisiones en Urología, sin recaida. JULIO/2011: MELANOMA EN PIEL DE REGION DORSAL (Seguía revisiones por múltiples nevus (más de 100) sobre todo en tronco) 1º EXÉRESIS SIMPLE (25/07/11): melanoma, Breslow 2,5 mm. Clark III. Con ulceración, + TC Sin enfermedad a distancia. -- AMPLIACIÓN DE MÁRGENES (-) Y BSGC (29/08/11): CENTINELA AXILAR IZQ: MICROMTS DE MELANOMA. 3º) LINFADENECTOMÍA AXILAR IZQ (26/09/11): (0/15). ---- Se desestimó adyuvancia con IFN a dosis altas por edad. (Seguimiento en Derma y C.Plástica)

Caso clinico (2) A los 3.5 años : DESDE ENERO/2014: MULTIPLES METÁSTASIS EN TRÁNSITO RESECADAS EN REGION PERIESCAPULAR: FEB- 2014: uno de 2cm y otro satélite de 5mm. (TAC entonces SIN ENF A DISTANCIA) OCT Y NOV/2014: 2 EXÉRESIS DE MÁS MTX EN TRÁNSITO. DIC 2014 Y ENERO-2015: Nueva CIRUGIA DE CUTÁNIDES, + COBERTURA CON AUTOINJERTO DE MUSLO. OCT-2015- Nueva exéresis de metastasis en tránsito en la zona (+ TAC OCT-215 SIN ENF A DISTANCIA) ENERO-2016: NUEVA CIRUGIA DE MTS CUTANEAS: (6 nódulos de metástasis de melanoma, cuatro subcutáneos y dos en dermis profunda que no alcanza los bordes de resección ( un nódulo subcutáneo a menos de 1 mm del borde quirúrgico medial ).

Caso clinico (3) ABRIL-2016: SE REMITE A ONCOLOGIA POR PROGRESION PULMONAR - TAC (ABRIL-2016) -Milimetricos nódulos pulmonares bilaterales de nueva aparición. Los mayores el Apical dcho de 8 mm) Apical iz de 6 mm), Basal anterior inferior LSD, Basal medial inferior LIIz

Caso clínico (4) PACIENTE ECOG 0, LDH NORMAL Y ENFERMEDAD ESCASA: CANDIDATO PARA INMUNOTERAPIA SE SOLICITA AUTORIZACION PARA TRATAMIENTO CON PEMBROLIZUMAB: que COMIENZA EN MAYO -2016 -- RECIBIDO POSTERIORMENTE B-RAF MUTADO --- Tras 4º:TAC (28-JULIO-2016): - RESPUESTA PULMONAR nódulos HAN DISMINUIDO DE TAMAÑO. - Pero APARICION DE VARIAS LESIONES FOCALES SOLIDAS ESPLENICAS compatibles con metastasis (En hígado hay varias lesiones hipodensas informados como quistes simples) PERO ESTE TAC CON MEJOR DEFINICION, LA LESION DEL SGM IV DE 16 mm SE ETIQUETA COMO METASTASIS

Caso Clínico (5) qué hacer? TAC DE DISTINTA DEFINICION, EXISTE RESPUESTA DE LOS NODULOS PULMONARES + LDH NORMAL + PACIENTE ASINTOMATICO. ANTE POSIBILIDAD DE PSEUDO-PROGRESION, SE DECIDE CONTINUAR TTO X 3 MESES (julio a octubre- 2016) EN TAC OCTUBRE-2016 HAY RESPUESTA COMPLETA DE LAS MTS PULMONARES PERO

Caso clinico (6) ACUDE A URGENCIAS EL 31-10, POR DOLOR ABDOMINAL + DIARREA ABUNDANTE Y FIEBRE DE 39ºc CON SINCOPE (EL 112 REGISTRA HIPOTENSION MARCADA) TAC (OCT-2016) DESAPARICION DE LOS NODULOS PULMONARES PREVIOS PERO Aparición de MASA HIPODENSA-implante de centro de aspecto necrótico, de 7x7 cm. en FII y que contacta con asas de delgado condicionado discreta dilatación segmentaria por probable suboclusión intestinal. + Aumento de las lesiones focales sólidas esplénicas (la mayor de 32 mm ) + En hígado persisten los quistes simples mm y la lesión sólida periférica en segmento 4 de 16 mm. Mínimo aumento (?) De lesión lítica inespecífica del hueso ilíaco de 8 mm. aprox. (antes 6,5 mm).

Caso clinico (7) Resolución Valorado en Comité, Se sugiere: PCR elevada en paciente con inmunoterapia, no se puede descartar por la imagen eventual microperforacion con abcesificación, persistiendo dolor abdominal a pesar de corticoides y antibióticos, y se decide CIRUGIA LAPAROTOMIA 5-12-2016: halla implante peritoneal infiltrando un asa de i.delgado, que se reseca. AP. METASTASIS DE MELANOMA ACTUALMENTE: Pendiente de recuperacion de complicaciones post-cirugia (precisó 2 cirugias x peritonitis x dehiscencia) con TAC mostrando multiples imágenes de abcesos abdominales PREVISTO INICIAR TTO CON DOBLE BLOQUEO ANTI BRAF-ANTI MEK

Tumor Immunology: Overview 3 Tumor Perforin granzyme Cytokines (IL-2) Resting T cell Activated T cell 2 T-cell clonal expansion Tumor antigen TCR 1 MHC B7 Dendritic cell CD28 Lymph node

PUNTOS DE CONTROL PARA LA INMUNOTERAPIA ganglio tumor

IPILIMUMAB El pionero Ab anti Cytotoxic T-Lymphocyte Associated Ag-4 (CTLA-4) Approved 2011 2013 at first line at Europe

Ipilimumab, gp100, or Both: OS in Advanced Melanoma Median OS, Mos Ipilimumab + gp100 (n = 403) 10.0 Ipilimumab alone (n = 137) 10.1 gp100 alone (n = 136) 6.4 100 OS (%) 80 HR 0.68 0.66 --- P Value <.001.003 --- ORR: 10.9% 60 2-yr OS, % Ipi + gp100 22% Ipi alone: 24% Gp100 alone: 14% 40 20 0 0 1 2 3 Yrs % OS, Hodi FS, et al. N Engl J Med. 2010;363:711-723. Yr 1 Ipi + gp100 4 Ipi + Placebo gp100 + Placebo 44 46 25

Phase II and Phase III Trials of Ipilimumab: OS Plateau at Yr 3 Proportion Alive 1.0 Median OS: 11.4 mos (95% CI: 10.7-12.1) 0.8 3-yr OS rate: 22% (95% CI: 20% to 24%) 0.6 0.4 0.2 Ipilimumab Censored 0 0 Pts at Risk, n Ipilimumab 1861 12 24 36 48 60 Mos 72 84 96 108 120 839 370 254 192 170 120 26 15 5 0 Schadendorf D, et al. J Clin Oncol. 2015;33:1889-1994. Slide credit: clinicaloptions.com

OS: 11.2 vs 9.1 PFS: 2.7 m

Que nos enseñó el Ipilimumab? Respuesta escasas (11-15%) MEJOR SI Biología Tumoral Favorable Bajo volumen tumoral, Normal LDH, Peor visceral. 25-30% control de la enfermedad muy prolongado SOLO CON 4 DOSIS (12 Semanas) ( PRECIO ) PRECISA TIEMPO (3 O MAS MESES) PARA VER RESPUESTA (no es buena opción si se requiere respuesta rápida) PATRON DE RESPUESTA INHABITUAL. Pseudoprogresion inicial antes de respuesta posterior (hasta 25% casos). Esperar PROBLEMATICA TOXICIDAD INMUNOMEDIADA: EFECTOS ADVERSOS RELACIONADOS CON SU MECANISMO DE ACCION Centros con experiencia por la toxicidad Y colaboración del paciente

Summary of CTLA-4 Blockade Immune-Mediated Toxicities Toxicity of ipilimumab appears to be dose related Common (> 20%) Rash, GI: Episcleritis/uveitis pruritus Fevers, chills, lethargy Diarrhea/colitis Occasional (3% to 20%) Hepatitis/liver enzyme abnormalities Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency Vitiligo Rare (< 2%) Pancreatitis Nephritis Neuropathies, Guillain-Barré, myasthenia gravis Lymphadenopathy (sarcoid) Thrombocytopenia Toxic epidermal necrolysis, Stevens-Johnson syndrome IrAEs occurred in about 64.2% of patients treated with ipilimumab in several phase IWeber -III studies of grade 3 andweber 4 events) JS, et al.(with J Clin20-30% Oncol. 2012;30:2691-2697. JS, et al. J Clin Oncol. 2015;[Epub ahead of print].

PUNTOS DE CONTROL PARA LA INMUNOTERAPIA Ganglio Tumor

PD-1 Inhibitors: Melanoma 2015 Nivolumab + Single agent (3 mg/kg q2w) for unresectable or metastatic melanoma with or without a BRAF V600 mutation **** Flat dose 240 mg c/2w ***** + In combination with ipilimumab for unresectable or metastatic melanoma Nivolumab 1 mg/kg + ipilimumab 3 mg/kg q3w x 4 then nivolumab 3 mg/kg q2w Pembrolizumab + Single agent (2 mg/kg q3w) for unresectable or metastatic melanoma

Estudios anti PD1 POST-IPI (PACIENTE IPI-REFRACTARIOS) NIVOLUMAB vs Chemotherapy; Checkmate-037 PEMBROLIZUMAB vs Chemotherapy; KEYNOTE-002: **** PRIMERA LINEA VS QUIMIOTERAPY; NIVOLUMAB vs Chemotherapy CheckMate 066: VS IPILIMUMAB PEMBRO vs Ipilimumab KEYNOTE-006: NIVO + IPI vs NIVO vs IPI Checkmate-067:

ANTI PD1: Nivolumab Pembrolizumab in Ipilimumab-Refractory Pts Comparison Pts, n (IPI-R) FDA-approved schedule ORR, % (95% CI) Grades 3/4 drug-related toxicities, % * 2º LINEA Nivolumab (Checkmate-037) Pembrolizumab (KEYNOTE-002) (2 doses) 120 (preliminary subset) 180 3 mg/kg IV every 2 wks 2 mg/kg IV every 3 wks 32 (24-41) 5 21 (15-28) 8

Phase III Checkmate-037: Nivolumab vs Chemotherapy in Ipilimumab-Refractory Pts Stratified by PD-L1 expression (+ vs - or indeterminate)*, BRAF wild type vs V600 mutant, best overall response prior to anti CTLA-4 (clinical benefit vs no clinical benefit) Pts with advanced melanoma who progressed on or after ipilimumab (and BRAF, if BRAF V600+) Nivolumab 3 mg/kg IV q2w (n = 268) Open Label Investigator s choice of chemotherapy: Dacarbazine 1000 mg/m2 q3w or Carboplatin AUC 6 IV + Paclitaxel 175 mg/m2 q3w (n = 102) Treat until Progression OR Unacceptable toxicity Pts receiving nivolumab may be treated beyond initial progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug *Positive: 5% tumor cell surface staining cutoff by IHC. Weber JS, et al. Lancet Oncol. 2015;16:375-384. Slide credit: clinicaloptions.com

Nivolumab vs Chemotherapy in Ipilimumab-Refractory Pts: ORR and Safety Treatment N CR + PR, n ORR*, % (95% CI) CR PR SD PD UNK Best Overall Response,* % Central review Nivolumab 120 38 (4 CR) 32 (24-41) 3 28 23 35 10 ICC 47 5 (0 CR) 11 (4-23) 0 11 34 32 23 *Confirmed response. Independent radiology review committee based on RECIST 1.1. Grade 3/4 toxicity incidence higher with chemotherapy (32%) vs nivolumab (9%) Most frequent adverse events of any grade ( 10%) Nivolumab: fatigue, pruritus, and diarrhea Chemotherapy: fatigue, nausea, vomiting, anemia, reduced appetite, diarrhea, constipation, arthralgia, and alopecia Weber JS, et al. Lancet Oncol. 2015;16:375-384. Slide credit: clinicaloptions.com

KEYNOTE-002: Pembrolizumab vs Chemotherapy in Ipi-Refractory Melanoma Stratified by ECOG PS (0 vs 1); LDH (normal vs 110% ULN); BRAF status (wild type vs V600 mutant) PHASE II: Pts with advanced melanoma who progressed on or after Ipi (and targeted therapy, if BRAF V600+) (N = 540) Pembrolizumab 2 mg/kg IV q3w (n = 180) Pembrolizumab 10 mg/kg IV q3w (n = 181) Investigators choice of chemotherapy* (n = 179) *Carboplatin + paclitaxel, paclitaxel alone, carboplatin alone, dacarbazine, or temozolomide. Pts with PD confirmed by independent central review could cross over to pembrolizumab treatment after the first 3-mo assessment. Primary endpoint: PFS, OS Ribas A, et al. Lancet Oncol. 2015;16:908-918. Secondary endpoints: ORR, DoR Slide credit: clinicaloptions.com

KEYNOTE-002: Efficacy and Safety ORR, % 100 80 PFS (%) An international, randomized phase II study in pts with advanced melanoma with PD within 24 wks after 2 Ipi doses 60 Grade 3/4 toxicity incidence higher with chemotherapy (26%) vs pembrolizumab (11% at 2 mg/kg and 14% at 10 mg/kg) Most frequent adverse events of any grade ( 10%) Pembro 2 mg/kg q3w 21 Pembro 10 mg/kg q3w 25 Chemotherapy 4 Pembrolizumab: fatigue, pruritus, and rash Chemotherapy associated primarily with grade 1/2 fatigue, nausea, vomiting, anemia, reduced appetite, alopecia 12 14 40 20 0 0 2 4 6 8 10 Mos Ribas A, et al. Lancet Oncol. 2015;16:908-918. 16 18 Slide credit: clinicaloptions.com

KEYNOTE-002: Efficacy and Safety NOT dose response relationship (Pembro at 2 mg/kg or 10 mg/kg did not affect outcomes) 100 PFS (%) 80 Results updated al European Society for Medical Oncology (ESMO) 2016 ORR, % PFS 2 years % OS m 24 m OS % Pembro 2 mg/kg q3w 22 16 13.4 36 Pembro 10 mg/kg q3w 26 22 14.7 38 Chemotherapy 4 <1 11 * 30 * 60 40 20 0 0 2 4 6 8 10 Mos Ribas A, et al. Lancet Oncol. 2015;16:908-918. 12 14 16 18 Slide credit: clinicaloptions.com

Estudios anti PD1 POST-IPI (PACIENTE IPI-REFRACTARIOS) NIVOLUMAB vs Chemotherapy; Checkmate-037 PEMBROLIZUMAB vs Chemotherapy; KEYNOTE-002: **** PRIMERA LINEA VS QUIMIOTERAPY; NIVOLUMAB vs Chemotherapy CheckMate 066: VS IPILIMUMAB PEMBRO vs Ipilimumab KEYNOTE-006: NIVO + IPI vs NIVO vs IPI Checkmate-067:

Phase III CheckMate 066: First-line Nivolumab vs Chemotherapy Stratified by PD-L1 status, M-stage Unresectable, treatment-naive stage III or IV melanoma; BRAF wild type; ECOG PS 0-1; 18 yrs of age or older (N = 418) Nivolumab 3 mg/kg IV q2w + Placebo IV q3w (n = 210; 206 treated) Placebo IV q2w + Dacarbazine 1000 mg/m2 IV q3w (n = 208; 205 treated) Treat until progression* or unacceptable toxicity * Pts may be treated beyond initial RECIST v1.1 defined progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug. Primary endpoint: OS Secondary endpoints: PFS, ORR, PD-L1 correlates Robert C, et al. N Engl J Med. 2015;372:320-330. Slide credit: clinicaloptions.com

First-line Nivolumab vs Chemotherapy: OS Objective RR: 40.0% with nivolumab vs 13.9% with chemo (P <.001) (respuesta en dias pocas semanas) Significantly better OS with nivolumab vs dacarbazine 100 HR 0.42 (99.79% CI: 0.25 0.73; P <.001) 1-yr OS: 73% Pts Surviving (%) 80 60 1-yr OS: 42% 40 Median OS, Mos (95% CI) 20 Nivolumab Dacarbazine NR 10.8 (9.3-12.1) 0 3 6 Robert C, et al. N Engl J Med. 2015;372:320-330. 9 M os 0 12 15 18 Slide credit: clinicaloptions.com

First-line Nivo vs Chemotherapy: PFS Pts Without Progression (%) 100 Nivolumab Dacarbazine 80 6-mo PFS: 48% 60 Median PFS, Mos (95% CI) 5.1 (3.5-10.8) 2.2 (2.1-2.4) HR: 0.43 (95% CI: 0.34-0.56; P <.001) Nivolumab (n = 210) 40 6-mo PFS: 19% 20 Dacarbazine (n = 208) 0 3 6 9 12 15 18 M os 0 Robert C, et al. N Engl J Med. 2015;372:320-330. Slide credit: clinicaloptions.com

PD-1/PD-L1 Blockade Immune-Mediated Toxicities Occasional (5% to 20%) Fatigue Rash: maculopapular and pruritus Topical treatments Diarrhea/colitis Initiate steroids early, taper Infusion reactions Endocrinopathies: thyroid, adrenal, hypophysitis Infrequent (< 5%) Pneumonitis Grade 3/4 toxicities uncommon slowly Hepatitis/liver enzyme abnormalities Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. Patnaik A, et al. ASCO 2012. Abstract 2512. Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465. Herbst RS, et al. ASCO 2013. Abstract 3000.

KEYNOTE-006: Pembrolizumab (2 Doses) vs Ipilimumab in Stage III/IV Melanoma A multicenter, randomized, phase III study (1º linea immuno) Stratified by ECOG PS (0 vs 1), line of therapy (first vs second), PD-L1 status (positive vs negative) Pembrolizumab 10 mg IV q2w for up to 2 yrs Unresectable stage III or IV melanoma; 1 prior therapy, excluding checkpoint inhibitors; ECOG PS 0-1; 18 yrs of age or older (N = 834) Pembrolizumab 10 mg IV q3w for up to 2 yrs Ipilimumab 3 mg/kg IV once q3w for 4 doses Primary endpoint: PFS, OS Secondary endpoint: ORR, DoR, safety Robert C, et al. N Engl J Med. 2015;372:2521-2532. Slide credit: clinicaloptions.com

KEYNOTE-006: Survival Efficacy at First Interim Analysis of Pembro vs Ipi PFS OS (%) 0 2 4 6 8 Mos OS 10 0 8 0 PFS (%) 10 0 8 0 6 0 4 0 2 0 0 1 0 1 2 6 0 4 0 2 0 0 1 4 0 2 4 6 8 10 Mos HR (95% CI) P Value Median OS (95% CI), Mos Rate at 12 Mos, % 12 14 16 18 Treatment Arm Median PFS Rate at (95% CI), 6 Mos, % Mos Pembro q2w 5.5 (3.4-6.9) 47.3 0.58 (0.46-0.72) <.00001 NR (NR-NR) 74.1 0.63 (0.47-0.83).00052 Pembro q3w 4.1 (2.9-6.9) 46.4 0.58 (0.47-0.72) <.00001 NR (NR-NR) 68.4 0.69 (0.52-0.90).0036 Ipi 2.8 (2.8-2.9) 26.5 NR (12.7-NR) 58.2 Robert C, et al. N Engl J Med. 2015;372:2521-2532 RESPUESTA EN LA PG SIGUIENTE. HR (95% CI) P Value Slide credit: clinicaloptions.com

Checkmate-067: Nivo + Ipi vs Nivo vs Ipi for First-line A randomized, double-blind phase III study Stratified by tumor PD-L1 status (positive vs negative/indeterminate), BRAF mutation status (V600 mutation positive vs wild type), and AJCC metastasis stage (M0, M1a, or M1b vs M1c) Unresectable, treatment-naive stage III or IV melanoma; ECOG PS 0-1; 18 yrs of age or older (N = 945) Nivo 1 mg/kg IV + Ipi 3 mg/kg IV every 3 wks for 4 doses Nivo 3 mg/kg IV every 2 wks until PD or unacceptable AE Placebo + Nivo 3 mg/kg IV every 2 wks for 4 doses Nivo 3 mg/kg IV every 2 wks until PD or unacceptable AE Placebo + Ipi 3 mg/kg IV every 3 wks for 4 doses Placebo IV every 2 wks until PD or unacceptable AE Primary endpoint: OS, PFS Secondary endpoint: ORR, OS by PD-L1, safety DOSIS IPI Y NIVO? Larkin J, et al. N Engl J Med. 2015;373:23-34.

Proportion Alive and Progression Free CheckMate 067: Improved PFS With Nivo + Ipi or Nivo Alone vs Ipi Alone Nivo + Ipi (n = 314) Nivo (n = 316) Ipi (n = 315) 11.5 (8.9-16.7) 6.9 (4.3-9.5) 2.9 (2.8-3.4) HR (99.5% CI) vs Ipi 0.42 (0.31-0.57)* 0.57 (0.43-0.76)* _ HR (95% CI) vs Nivo 0.74 (0.60-0.92) Median PFS, mos (95% CI) 1.0 0.8 0.6 0.4 Nivo + Ipi Nivo Ipi 0.2 0 0 3 6 *Stratified log-rank P <.00001 vs Ipi. 9 12 15 18 Mos Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo. 21

CheckMate 067: Nivo + Ipi Provides Most Benefit for PD-L1lo, Similar to Nivo for PD-L1hi PD-L1 5%* Median PFS, Mos HR Nivo + Ipi 14.0 0.40 Nivo alone 14.0 0.40 Ipi alone 3.9 -- 100 60 40 80 60 40 20 20 0 0 0 3 6 9 Mos 12 15 17 Median PFS, Mos HR 0.42 Nivo + Ipi 11.2 0.60 Nivo alone 5.3 2.8 -Ipi alone 100 PFS (%) 80 PFS (%) PD-L1 < 5%* 0 3 6 9 12 Mos 15 18 21 *Per validated PD-L1 IHC assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells. Larkin J, et al. N Engl J Med. 2015;373:23-34. Slide credit: clinicaloptions.com

CheckMate 067: Treatment-Related AEs Associated With Nivo and Ipi Select Treatment-Related AEs, % Nivo + Ipi (n = 313) Nivo (n = 313) Ipi (n = 311) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any select AE 88 40 62 8 74 19 Skin Pruritus Rash Maculopapular rash 59 33 28 12 6 2 3 2 42 19 22 4 2 0 <1 <1 54 35 21 12 3 <1 2 <1 Gastrointestinal Diarrhea Colitis 46 44 12 15 9 8 20 19 1 2 2 <1 37 33 12 12 6 9 Hepatic ALT increase AST increase 30 18 15 19 8 6 6 4 4 3 1 1 7 4 4 2 2 <1 Endocrine Hypothyroidism 30 15 5 <1 14 9 <1 0 11 4 2 0 Pulmonary Pneumonitis 7 6 1 1 2 1 <1 <1 2 2 <1 <1

Ipilimumab plus pembrolizumab?? ASCO 2016 A Non-randomized expansion cohort combining pembrolizumab pembrolizumab (2 mg/kg every three weeks) + ipilimumab (1 mg/kg for four doses) Median follow-up of 10 months, the ORR 57 % (including 10 % RC and 47 % PR). PFS was 70 % at 6 months. Grade 3 or 4 toxicity was observed in 42 % of patients; immune-related adverse events were seen in 58 % of patients, and 25 % experienced grade 3 or 4 immune-related toxicity. Only 25 % of patients needed to stop therapy due to toxicity.

MULTIPLES PREGUNTAS Y DUDAS

Desmontar lo que sabíamos con el Ipi?? IPILIMUMAB Respuesta (11-15%), 25-30% prolongado RESPUESTA PRECISA TIEMPO (3 O MAS MESES) PATRON DE RESPUESTA INHABITUAL. SOLO CON 4 DOSIS (12 Semanas) - Precio* TOXICIDAD SERIA INMUNOMEDIADA: NIVO PEMBROLIZUMAB RESPUESTAS > 40% (TB VISCERAL) RESPUESTA RAPIDA ( B-RAF?) Prolongadas? Poco tiempo

ANTI-PD1 OR ANTI-BRAFi? No Association Between BRAF or NRAS Mutation and Response to Ipilimumab BRAF-i Followed by Ipilimumab or Ipilimumab Followed by a BRAFi: OS: better for ipi in first line BRAF inhibitor, ipilimumab: 9.9 mos (95% CI: 5.8-14.0) Ipilimumab, BRAF inhibitor: 14.5 m (95% CI: 11.1-17.9) Median OS in patient subgroups (ipi-brafi vs BRAFi-ipi) Elevated LDH: 14 (95% CI: 13.4-14.6) vs 7.5 mos (95% CI: 3.6-11.4) Brain metastasis: 12.3 (95% CI: 7.9-16.7) vs 7.5 mos (95% CI: 5.6-9.4) NO DATOS CON ANTI-PD1 (los datos del pembro que eran mejor en B-RAF MUTADOS ANTES DE TERAPIA ANTI-BRAF)

Phase III Dabrafenib/Trametinib Nivo/Ipi vs Nivo/Ipi Dabrafenib/Trametinib Sequencing study combining immunotherapy and BRAF/MEK Progression inhibition in stage III/IV melanoma Unresectable, treatment-naive stage III or IV melanoma; ECOG PS 0-1; BRAF V600E/K mutation (Planned N = 300) Dabrafenib 150 mg PO BID + Trametinib 2 mg PO QD Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w Dabrafenib 150 mg PO BID + Trametinib 2 mg PO QD Primary endpoint: 2-yr OS rate Secondary endpoints: PFS, ORR, safety ClinicalTrials.gov. NCT02224781. Slide credit: clinicaloptions.com

Desmontar lo que sabíamos con el Ipi?? IPILIMUMAB Respuesta (11-15%), 25-30% prolongado RESPUESTA PRECISA TIEMPO (3 O MAS MESES) PATRON DE RESPUESTA INHABITUAL. SOLO CON 4 DOSIS (12 Semanas) - Precio* TOXICIDAD SERIA INMUNOMEDIADA: NIVO PEMBROLIZUMAB RESPUESTAS > 40% (TB VISCERAL) RESPUESTA RAPIDA ( B-RAF?) Prolongadas? Poco tiempo PRACTICAMENTE NO PSEUDO-PROGRESION TTO HASTA PROGRESION?? Precio+++

Hay Pseudoprogresión (patrón atipico de respuesta?) con antipd1? Immune-related response criteria have been proposed with ipilimumab and potentially other immunotherapies. Of 655 patients with pembrolizumab; who survived at least 12 weeks, ONLY 14 % had progressive disease by RECIST but not by immune-related response criteria (And OS 2-year was 37.5%, vs 17.3 % in those with progressive disease based upon both criteria). BUT Among the 327, pseudoprogression ( 25 percent increase in tumor burden NOT confirmed at repeat imaging) was observed ONLY in 24 cases (7%), of which 15 occurred by 12 weeks of imaging, and nine were later. (93% WERE AUTHENTIC PROGRESSION )

Expert opinion: In a patient who has minor to moderate increase in disease burden by imaging, but who is otherwise feeling well, with no evidence of decline, continuing treatment with the same immunotherapy is reasonable until the time of a confirmatory scan. However, it is important to emphasize that this is a relatively uncommon phenomenon, and patients who are experiencing increasing cancer-related symptoms or clinical decline should not be continued on the same treatment. OTRA COSA ES QUE TENGAMOS ALGO MEJOR QUE OFRECERLES

Tratamiento hasta progresión?? Para qué? Si se retira van igual? A retrospective, unpowered analysis suggested that these patients still did at least as well as those patients who received the full treatment Entonces xq no quitarlo antes? Cuando?

Desmontar lo que sabíamos con el Ipi?? IPILIMUMAB Respuesta (11-15%), 25-30% prolongado NIVO PEMBROLIZUMAB RESPUESTAS > 40% (TB VISCERAL) RESPUESTA RAPIDA ( B-RAF?) Prolongadas? Poco tiempo RESPUESTA PRECISA TIEMPO (3 O MAS MESES) PATRON DE RESPUESTA INHABITUAL. PRACTICAMENTE NO PSEUDO-PROGRESION TTO HASTA PROGRESION?? Precio+++ SOLO CON 4 DOSIS (12 Semanas) Precio* MUCHO MENOS TOXICO (PERO NO ATOXICO) PS 0-1 DETERMINAR PD-L1?? TOXICIDAD SERIA INMUNOMEDIADA:

RECORDAR QUE EN EL Checkmate-067 ESTUDIO 3 BRAZOS CON IPI + NIVO, EL PUNTO DE CORTE ERA 5%

PDL-1: Expert opinion Overall, most trials (either retrospective or prospective) PD-L1 status have shown trends for increased response rates to PD-1 blockade in PD-L1 "positive" tumors (+ longer PFS, and longer overall survival compared with tumors that did not express PD-L1) BUT patients PDL-1 negative had too good responses with nivolumab in other trials, and near the same survival For melanoma, PD-L1 shouldn t determine whether we give nivolumab monotherapy, Regardless of PD-L1 status, you live longer with nivolumab. After the results of Checkmate-067, only if you are considering combination of Ipilimumab + nivolumab, it would be important to know PDL-1 Status. However, patients with high-risk characteristics, for which a rapid response is needed, should receive a combination of nivolumab and ipilimumab nevertheless PDL1-Status?. (?)

RECOMENDACIONES DE EXPERTOS: CASOS CLINICOS INMUNOTERAPIA?

Treatment of a Pt With Regional In-Transit Disease A 73-yr-old man previously treated for ulcerated melanoma on his sole, and subsequently with cryotherapy for in-transit lesions now presents with multiple new lesions but no evidence of distant metastatic disease Workup: BRAF WT, ECOG PS 0, LDH normal Expert recommendations Expert 1 Expert 2 Nivo or Pembro Ipi + Nivo Expert 3 Expert 4 Nivo or Pembro Nivo or Pembro Expert 5 Pembro Slide credit: clinicaloptions.com

Caso clinico 2: Paciente que va bien SIN INMUNOTERAPIA 85 AÑOS (HTA Y osteoporosis) Histerectomia x miomas. MELANOMA MALIGNO MID (extirpado jun-2010) (a los 78 años) Exéresis local (1/06/10): AP: melanoma maligno nodular, ulcerado, Breslow de 7 mm TC craneal y TAP (17/06/10): en FID imagen de defecto de repleción en ileón distal con imagen de masa de 2cm en la válvula ileocecal, ((1º COLONO DIC-2010: Melanosis coli, sin otras alts). Ampliación e injerto (30/06/10): AP: melanoma maligno nodular, quedando a menos de 1 mm del otro extremo de resección. NO SE HIZO BSGC X EDAD.

Caso clinico (2) SEPT-2010: APARICION DE LESIONES SATÉLITES, PET-TC (6/09/10): aumento del metabolismo solo en 1/3 inferior MID ; sin enfermedad a distancia. PAAF ADENOPATIA INGUINALES (-). Estadio clínico: pt4acn2cm0 (IIIB). RECHAZO AMPUTACION Y TTO INTRAARTERIAL QT PALIATIVA DTIC (reducción 20% inicial por edad) de oct-2010 a marzo-2011 x 8 ciclos. Toxic: náuseas G1, Astenia marcada, disgeusia. - Respuesta: Leve MEJORIA DE LAS LESIONES CUTANEAS, QUE FUERON DESAPARECIENDO (aplanándose, quedando como una peca residual) en los MESES SIGUIENTES

Caso clinico (3) evolucion Anticoagulada en marzo 2012 x FA Desde mayo-2012 precisó transfusión por anemia progresiva desde inicio de Sintrom + SOH (+ 3 muestras), COLONOSCOPIA (31-10-202) TUMORACION POLIPOIDEA ADYACENTE A VALV. ILEOCECAL de unos 3 cm (AP. Mts de melanoma) TAC (dic-2012) SIN CAMBIOS (EN LA IMAGEN QUE SE ATRIBUIA A LIPOMA DESDE EL DGº EN 2010) CUTANIDES MID SEGUIAN EN REMISION. CIRUGIA: 8/2/13 Hemicolectomia derecha. (AP: MTS DE MELANOMA) ENERO-2017 NO HAY PROGRESION DE CUTANIDES NI RECAIDA DE ENFERMEDAD

INITIAL TREATMENT of a Pt With Metastatic Melanoma A 47-yr-old woman was recently diagnosed with stage IV melanoma with multiple liver, lung, and bone metastases; she is symptomatic with mild bone pain which she manages with daily acetaminophen Expert recommendations: BRAF Wild Type (ECOG PS 1, LDH normal) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi + Nivo Ipi + Nivo Ipi + Nivo Nivo or Pembro Pembro

INITIAL TREATMENT of a Pt With Metastatic Melanoma A 47-yr-old woman was recently diagnosed with stage IV melanoma with multiple liver, lung, and bone metastases; she is symptomatic with mild bone pain which she manages with daily acetaminophen Expert recommendations: BRAF Wild Type (ECOG PS 1, LDH normal) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi + Nivo Ipi + Nivo Ipi + Nivo Nivo or Pembro Pembro BRAF V600 Mutant (ECOG PS 1, LDH normal) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi + Nivo Ipi + Nivo Ipi + Nivo Nivo or Pembro Pembro

Initial Treatment of a Pt with Metastatic Melanoma and ECOG PS of 2 A 47-yr-old woman was recently diagnosed with stage IV melanoma with multiple liver, lung, and bone metastases; she is symptomatic with an ECOG PS of 2 Expert recommendations: BRAF Wild Type (ECOG PS 2, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi + Nivo Ipi + Nivo Ipi + Nivo Nivo or Pembro Pembro Slide credit: clinicaloptions.com

Initial Treatment of a Pt with Metastatic Melanoma and ECOG PS of 2 A 47-yr-old woman was recently diagnosed with stage IV melanoma with multiple liver, lung, and bone metastases; she is symptomatic with an ECOG PS of 2 Expert recommendations: BRAF Wild Type (ECOG PS 2, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi + Nivo Ipi + Nivo Ipi + Nivo Nivo or Pembro Pembro BRAF V600 Mutant (ECOG PS 2, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Dabrafenib + trametinib Dabrafenib + trametinib Ipi + Nivo Dabrafenib + trametinib Dabrafenib + trametinib Slide credit: clinicaloptions.com

PROGRESSION after First-line Anti PD-1 Therapy The PREVIOUS 47-yr-old pt elected to be treated with pembrolizumab; she does well with a PR, but 15 mos later, her condition worsens and scans show progression BRAF V600 Mutant (ECOG PS 1, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Slide credit: clinicaloptions.com

PROGRESSION after First-line Anti PD-1 Therapy The PREVIOUS 47-yr-old pt elected to be treated with pembrolizumab; she does well with a PR, but 15 mos later, her condition worsens and scans show progression BRAF Wild Type (ECOG PS 1, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Ipi Ipi + Nivo Ipi + Nivo Ipi Ipi BRAF V600 Mutant (ECOG PS 1, LDH high) Expert 1 Expert 2 Expert 3 Expert 4 Expert 5 Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Dabrafenib + trametinib Slide credit: clinicaloptions.com NO TENEMOS DATOS EN ESTE ESCENARIO

CheckMate-064: Sequential Treatment With Ipi and Nivo in Advanced Melanoma Randomized phase II trial Unresectable, stage III or IV melanoma; 1 prior systemic treatment for advanced disease; ECOG PS 0-1 (N = 140) Nivo 3 mg/kg q2w for 6 cycles (n = 70) Ipi 3 mg/kg q4w for 4 cycles Ipi 3 mg/kg q4w for 4 cycles (n = 70) Nivo 3 mg/kg q2w for 6 cycles Induction 1 Induction 2 Nivo 3 mg/kg q2w until progression/ unacceptable toxicity Primary endpoint: incidence of grade 3 AEs during induction Secondary endpoints: ORR (Wks 25 and 33), rate of PD (Wks 13 and 25) Hodi FS, et al. European Cancer Congress 2015. Abstract 23LBA. Slide credit: clinicaloptions.com

CheckMate-064: Results Incidence of treatment-related 3 AEs during induction Nivo Ipi (n = 68): 50.0% Ipi Nivo (n = 70): 42.9% No treatment-related deaths in either arm ORR at Wk 25 (all PR) Nivo Ipi (n = 68): 41.2% Ipi Nivo (n = 70): 20.0% Hodi FS, et al. European Cancer Congress 2015. Abstract 23LBA. Slide credit: clinicaloptions.com

Second line immunotherapy? Expert opinion Given the nearly identical structure, and clinical outcomes between pembrolizumab and nivolumab, there is no role in the clinical setting for transition from 1 monotherapy to this similar monotherapy An appropriate second-line consideration in this setting will be treatment with ipilimumab There have been no studies of ipilimumab for patients who have progressed while on PD-1. However, it is believed ipilimumab can be effective in some patients after progression while on PD-1. There have been no studies of combination of ipilimumab + nivolumab in this scenario

CONCLUSIONES (Uptodate) y MIAS ANTI PD1: PembrolizumabANTI PD1: Pembrolizumab and nivolumab, are the preferred immunotherapies in patients with advanced melanoma Ipilimumab, may retain a role in combination with anti-pd-1 antibodies at first line but with much greater toxicity Molecularly targeted therapy against the MAP kinase pathway is an important option of patients with a characteristic BRAF V600 mutation. The optimal sequencing of targeted therapy and immunotherapy has not been definitively established. For good PS patients without a V600 BRAF mutation, we recommend immunotherapy that includes an anti-pd-1 antibody rather than ipilimumab, high-dose IL-2 or chemotherapy (Grade 1A). The combination of nivolumabthe combination of nivolumab plus ipilimumab, if available, rather than an anti-pd-1 antibody as monotherapy Based its possible In high risk patients (Grade 2B) upon lower-level evidence, there is consensus that the intervention is appropriate.

Conclusiones (2) However, long-term follow up is still pending, which is needed to fully assess the benefit of PD-1 blockade Despite the low toxicity of PD-1 inhibitors, AEs can still be in rare cases severe and even lethal. Patients and treating physicians have to be aware of possible immune-related AEs and sufficient knowledge and experience The combination of PD-1 inhibitors and anti-ctla-4 antibody has just been approved and will also play a role in the future; it is still unclear in which patient population At present, it seems patients with PD-L1 negative tumors benefit most from the combination therapy. There are still a substantial number of patients who show innate resistance to any approved immunotherapy

Que necesitamos? SENTIDO COMUN Estudios de Grupos cooperativos, que respondan preguntas clínicas Definir el mejor tratamiento para cada paciente según factores pronósticos (de paciente y del tumor) Ensayos sobre duración de tratamientos con antipd1 (sostenibilidad del sistema de salud) Ensayos de tratamiento combinado (sucesivo) de terapias dirigidas?? (y en cuanto se obtenga respuesta mantenerla con inmunoterapia) Ensayos de inmunoterapia + quimioterapia?

. NO SER TALIBANES DE LA INMUNOTERAPIA "There is no better targeted therapy than to have a T cell that has a T-cell receptor that specifically recognizes a specific tumor antigen??" ANTONI RIBAS TB TENEMOS LA TERAPIA DIRIGIDA USEMOS AMBAS DE LA MEJOR MANERA POSIBLE

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PUNTOS DE CONTROL PARA LA INMUNOTERAPIA Ganglio Tumor