Diapositiva 1 - Foro de Debate en Oncologia
Transcripción
Diapositiva 1 - Foro de Debate en Oncologia
Combinaciones Terapéuticas: el principio del fin del melanoma o del SNS Posibilidades ilimitadas de combinacion Combinación con quimioterapia • Estudios preclínicos han demostrado que – La quimioterapia aumenta liberación de antígenos que inician células T – Quimioterapia sensibiliza células a la muerte por linfocitos T – Quimioterapia destruye población Treg • Algunas quimioterapias pueden por tanto aumentar eficacia de ipilimumab • Hay datos disponibles de la asociación con – DTIC – Temozolomida – Fotemustina – Cisplatino y etoposido Reck M, et al. Ann Oncol. 2012 Aug 2. [Epub ahead of print] Robert C, et al. N Engl J Med 2011;364(26):2517–26 Di Giacomo AM, Lancet Oncol 2012 ;13(9):879–86 Patel SP, et al. Presented at ESMO 2012. P1126 Combinación con radioterapia • Modelo de ratón con carcinoma de mama muy poco inmunogenico – Bloqueo de CTLA-4 no afecta crecimiento ni supervivencia en el ratón – La radioterapia retrasa crecimiento tumoral tanto sola como asociada a anti-CTLA-4 – Supervivencia mejor para los tratados con combinación – El aumento de supervivencia se asocio a reducción de metástasis pulmonares mediado por linfocitos T lgG 9H10 RT+lgG RT+9H10 125 CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4; igG = immunoglobulin isotype G; RT = radiotherapy; 9H10 = monoclonal antibody; against CTLA-4 Survival (%) 100 75 50 25 0 25 30 35 40 45 50 55 60 Days post-tumour inoculation 65 Demaria S, et al. Clin Cancer Res 2005;11:728–734 Efectos inmunológicos de la inhibición b-raf Asociación dabrafenib + Ipilimumab • Triplete se asoció a colitis grado 3 con perforación en 2/7 • Doblete sin DLT Puzanov I et al. ASCO 2014 Combinación con agentes hipometilantes Bases preclínicas de la combinación con inmunoterapia • Los modelos preclínicos demuestran potenciación de la combinación de inmunoterapias400 300 Hamster IgG 200 BL6/GM + Hamster IgG Anti-CTLA4 BL6/GM + Anti-CTLA4 100 40 30 20 10 50 (0/5) 0 Day 4 Post-Challenge Melanoma murino con GVAX Davila E, et al. Cancer Res 2003;63(12):3281-8 Van Elsas A, et al. J Exp Med1999;190(3):355-66 Supervivencia Ipilimumab interleuquina • El seguimiento a largo plazo de el estudio fase II con 36 pacientes tratados con ipilimumab e interleuquina demuestra una tasa de respuestas completas superior a la esperada con un 25% supervivientes a 5 años Ipilimumab + gp100 vaccine Ipilimumab + IL-2 Ipilimumab dose escalation Peter A. Prieto et al. Clin Cancer Res 2012;18:2039-2047 Checkpoints actúan en diferentes compartimentos Creelan BC. Cancer Control 2014:21;80-89 Sequenced Therapy Concurrent Therapy Diseño del estudio CA209-004 Cohort 1 (N = 14) Nivo 0.3 + Ipi 3 Q3W x4 Nivo 0.3 Q3W x4 Nivo 0.3 + Ipi 3 Q12W x8 Cohort 2 (N = 17) Nivo 1 + Ipi 3 Q3W x4 Nivo 1 Q3W x4 Nivo 1 + Ipi 3 Q12W x8 Cohort 2a (N = 16) Nivo 3 + Ipi 1 Q3W x4 Nivo 3 Q3W x4 Nivo 3 + Ipi 1 Q12W x8 Cohort 3 (N = 6) Nivo 3 + Ipi 3 Q3W x4 Nivo 3 Q3W x4 Nivo 3 + Ipi 3 Q12W x8 Cohort 8 (N = 41) Nivo 1 + Ipi 3 Q3W x4 Cohort 6 (N = 17) Cohort 7 (N = 16) Prior standard ipilimumab therapy Nivo 3 Q2W x ≤48 Nivo 1 Q2W x ≤48 Nivo 3 Q2W x ≤48 All dose units are mg/kg. Ipi = ipilimumab; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks; Q12W = every 12 weeks CA209-004 Supervivencia 100 1-yr OS 94% 2-yr OS 88% 90 80 1-yr OS 85% OS (%) 70 2-yr OS 79% 1-yr OS 70% 60 50 40 30 Censored Cohorts 2 (Nivo 1 + Ipi 3) Concurrent Cohorts 1–3 Sequenced Cohorts 6–7 20 10 0 0 Patients at Risk Cohort 2 (Nivo 1 + Ipi 3) Concurrent Cohorts 1–3 Sequenced Cohorts 6–7 17 53 33 3 6 17 52 31 9 17 49 25 12 16 47 25 15 16 45 23 18 21 14 42 20 14 37 12 24 14 30 8 27 30 Month 13 25 0 33 7 16 0 36 4 11 0 39 42 45 48 3 7 0 3 5 0 3 5 0 0 1 0 0 1 0 0 0 0 Cohort 2 dose is similar to the dose/schedule used in phase 3 clinical studies June 2014 data analysis. Kluger et all. Oral presentation. SMR 2014 CA209-004 toxicidad Patients with an event, % All drug-related AEs Rash Pruritus Fatigue Diarrhea Nausea Lipase increased Pyrexia AST increased ALT increased Amylase increased All Concurrent Cohorts (N = 94) Any Grade Grade 3/4 97 64 64 6 52 0 45 1 38 7 23 2 22 15 22 0 19 11 18 12 17 6 All Sequenced Cohorts (N = 33) Any Grade 85 24 21 21 12 9 18 3 0 3 9 Grade 3/4 24 0 0 0 0 0 12 0 0 0 2 Sorted from high to low by total AEs of any grade reported in all concurrent cohorts (1–3 and 8; N = 94). ALT = alanine aminotransferase; AST = aspartate aminotransferase. April 2014 data analysis Kluger et all. Oral presentation. SMR 2014 Postow et all. NEJM. April 2015 CheckMate CA209-069: Estudio fase II randomizado Eligible patients with unresectable stage III or IV melanoma • • • Treatment-naïve BRAF WT (N = 100) or MT (N = 50) Stratified by BRAF status Arm A R 2:1 NIVO 1 mg/kg + IPI 3 mg/kg Q3W x4 NIVO 3 mg/kg Q2W Treat until: disease progressiona or unacceptable toxicity Double-blind Arm B Placebo + IPI 3 mg/kg Q3W x4 Placebo Q2W Primary endpoint: aTreatment beyond initial investigator-assessed RECIST v1.1- defined progression is permitted in patients experiencing clinical benefit and tolerating study therapy. Arm B patients have option to receive nivolumab monotherapy after progression. Upon confirmed progression and change of treatment, all patients are unblinded. MT = mutation; PFS = progression-free survival; Q3W = every 3 weeks; WT = wild type • ORR in BRAF WT patients Secondary endpoints: • PFS in BRAF WT patients • ORR and PFS in BRAF MT patients • Safety 15 Respuestas objetivas SLP en pacientes BRAF WT Death or disease progression, n/N Median PFS, mo (95% CI) NIVO + IPI 30/72 NR IPI monotherapy 25/37 4.4 (2.8-5.7) Patients Alive and Progression-Free (%) 100 90 80 70 HR 0.40 (95% CI, 0.23, 0.68; P < 0.001) 60 50 NIVO + IPI (N = 72) 40 30 20 IPI (N = 37) 10 0 0 Patients at risk 3 6 NIVO + IPI 72 54 45 IPI 37 20 9 9 12 15 18 38 20 1 0 6 2 0 0 PFS (Months) • Similar PFS among BRAF MT patients (8.5 mo for NIVO + IPI, 2.7 mo for IPI alone) Database lock: January 30, 2015 Resumen de seguridad NIVO + IPI (N = 94)a Patients Reporting, n (%) IPI (N = 46)a Any Grade Grade 3–4 Any Grade Grade 3–4 Treatment-related AEs 86 (91) 51 (54) 43 (93) 11 (24) Treatment-related AEs leading to discontinuation 44 (47) 36 (38) 8 (17) 6 (13) Treatment-related death aSafety 3 (3) 0 was evaluated in all patients who received at least one dose of study treatment • Summary of treatment-related deaths (n = 3) ‒ History of cardiac issues; death due to ventricular arrhythmia, 29 days after last treatment ‒ Sudden death 69 days after last treatment, while patient was clinically improving from pneumonitis/iatrogenic pneumothorax ‒ Sudden death 3 days after resolution of grade 3 pneumonia and grade 4 hypercalcemia, 86 days after last treatment Importantes costes • Para el paciente – Mas del doble de toxicidades grado 3-4 – Mas del doble de interrupciones de tratamiento • Para el sistema sanitario – Nivolumab (Opdivo) 12.500$ mes de tratamiento (150.000$ año) – Pembrolizumab (Keytruda) 12.500$ mes de tratamiento (150.000$ año) – Ipilimumab (Yervoy) 30.000$ ciclo de tratamiento (120.000$ año) ¿Es mejor combinación que monoterapia? KEYNOTE-006 (AACR 2014) ORR OS Pembro ipi-naïve (SMR 2014) ipi-nivo Cohort 8 ipi-naïve (SMR 2014) Pembro 10q2 Pembro 10q3 Ipi 34% 33% 12% 39% 40% 44% (vs 43% all concurrent) 5% CR 6% CR 1% CR 10% CR 8% CR 7% CR (vs 13% all concurrent) 74% at 12 mos 68% at 12 mos 58% at 12 mos Nivolumab 74% at 12 mos 73% at 12 mos ~80% at 9 mos (16 pts at risk) ?? At 12 mos (0 pts at risk) Grade 3-4 TRAEs Grade 3-4 TRAEs Grade 3-4 TRAEs Grade 3-4 TRAEs Grade 3-4 TRAEs Grade 3-4 TRAEs 11% 7% 18% 15% 12% 66% Discon due to AEs: Discon due to AEs: Discon due to AEs: Safety CheckMate 066 BRAF wt (SMR 2014) 4% 7% 9% Discon due to AEs: Discon due to AEs: Discon due to AEs: 6% 2% 23% 1 death Población CheckMate 069 mas favorable ChkMt 004 Cohort 8 CheckMate 069 (ph2) BRAF WT Patients All Randomized Patients PEM 10q2 (N=279) PEM 10q3 (N=277) IPI (N=278) 67 61 63 62 66/34 68/32 58/42 63/37 58/42 78 90 81 96 97 95 43 46 45 65 68 64 NIVO + IPI (N = 41) NIVO + IPI (N = 72) IPI (N = 37) NIVO + IPI (N = 95) IPI (N = 47) Age, median (yr) 55 66 69 64 Male/female (%) 44/56 67/33 62/38 AJCC stage IV (%) 89 M1c stage (%) ECOG performance status (%) 0 47 1 ≥2 Baseline LDH levels (%) ≤ULN >ULN History of brain metastases (%) BRAF V600 mutant (%) No prior systemic therapy (%) KEYNOTE-006 (ph3) Total (N = 142) 46 67/33 66 86 81 83 79 82 87 68 68 29 13 19 15 21 17 30 32 32 - 1 0 2 0 1 - - - 61 79 81 74 77 75 64 63 64 39 21 19 25 23 25 33 35 33 6 0 4 0 3 8 10 10 29 0 0 24 21 23 35 35 39 49 100 100 100 100 100 58 60 57 Tasas de Respuesta CheckMate 69 “investigator assessed” vs Keynote 006 “Central review” ChkMt 004 Cohort 8 ORR, % (95% CI) CheckMate 069 BRAF WT Patients KEYNOTE-006 BRAF MT Patients NIVO + IPI (N=72) IPI (N=37) NIVO + IPI (N=23) IPI (N=10) PEM 10q2 (N=279) PEM 10q3 (N=277) IPI (N=278) PEM vs IPI PEM vs IPI 44 61 (49, 72) 11 (3, 25) 52 (31, 73) 10 (0, 45) 34 (28, 40) 33 (27, 39) 12 (8, 16) 41 vs 13 21 vs 6 0.00013 0.00002 5 6 <0.001 Not evaluated Best overall response, % 22 0 22 0 Partial response 39 11 30 10 Stable disease 12 35 13 10 14 41 22 70 12 14 13 10 Progressive disease Unable to determine BRAF MT prior NIVO + IPI (N=41) P value for comparison Complete response BRAFM T naive 7 1 Supervivencia libre de progresión Keynote 006 incluye pacientes de primera y segunda línea ChkMt 004 Cohort 8 NIVO + IPI (N=41) Median PFS, months (95% CI) HR (95% CI) P value for comparison 6 month PFS rate (95% CI) ? CheckMate 069 BRAF WT Patients KEYNOTE-006 BRAF MT Patients NIVO + IPI (N=72) IPI (N=37) NIVO + IPI (N=23) IPI (N=10) PEM 10q2 (N=279) PEM 10q3 (N=277) IPI (N=278) NR 4.4 (2.85.7) 8.5 (?) 2.7 (?) 5.5 (3.4, 6.9) 4.1 (2.9, 6.9) 2.8 (2.8, 2.9) 0.58 (0.47, 0.72) - 0.40 (0.23, 0.68) ? 0.58 (0.46, 0.72) - 0.0006 ? 0.00001 0.00001 47.3 (41.2, 53.2) 46.4 (40.3, 52.3) ? ~68% (est) ~30% (est) ? ? 26.5 (20.9, 32.4) Seguridad CheckMate 069 Patients Reporting, n (%) NIVO + IPI (N = 94)a KEYNOTE-006 IPI (N = 46)a PEM 10q2 (N=278) PEM 10q3 (N=277) IPI (N=256) Any Grade Grade 3–4 Any Grade Grade 3–4 Any Grade Grade 3–4 Any Grade Grade 3–4 Any Grade Grade 3–4 Treatment-related AEs 86 (91) 51 (54) 43 (93) 11 (24) 221 (80) 31 (11) 202 (73) 18 (7) 187 (73) 45 (18) Treatment-related AEs leading to discontinuation 44 (47) 36 (38) 8 (17) 6 (13) 24 (9) 19 (7) 11 (4) 9 (3) 19 (7) 12 (4) Treatment-related death 3 (3) 0 0 0 1 (<1) Supervivencia a largo plazo CA209-003 de Nivolumab Mas de un tercio de los pacientes se sobre-tratarían y expondrían a toxicidad de forma innecesaria Hodi, S. SMR 2014 Conclusiones • Las terapias de combinación son extraordinariamente atractivas en el tratamiento del melanoma metastásico • Los incrementos de supervivencia parece que corren parejos a incrementos en la toxicidad • Para no sobre-tratar a una considerable proporción de pacientes es necesario – Abordaje secuencial – Identificación de factores predictivos