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Perspectivas A ctuales del Tratamiento con Inmunoterapia en Melanoma Adyuvante

Perspectivas A ctuales del Tratamiento con Inmunoterapia en Melanoma Adyuvante. Gabriela Cinat Jefa de Oncologia de la Unidad Funcional de Melanoma y Sarcoma Instituto de Oncologia Angel H. Roffo Universidad de Buenos Aires, Argentina.

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Perspectivas A ctuales del Tratamiento con Inmunoterapia en Melanoma Adyuvante

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  1. PerspectivasActuales del Tratamiento con Inmunoterapiaen Melanoma Adyuvante Gabriela Cinat Jefa de Oncologia de la Unidad Funcional de Melanoma y Sarcoma Instituto de OncologiaAngel H. Roffo Universidad de Buenos Aires, Argentina Contiene información e imágenes con permiso para su utilización como fuente 1506LA1901651-01

  2. Overall Survival for Metastatic Melanoma before 2011 Presented By Caroline Robert at 2017 ASCO Annual Meeting

  3. Two Scenarios Adjuvant Melanoma Nivolumab Metastatic Melanoma Pembrolizumab Nivo+Ipi Nivolumab Ipilimumab

  4. Adjuvant Treatment: CheckMate 238 NivovsIpiPhase 3 Trial (Updated Results 24 mo) Weber et al. ASCO 2018

  5. Adjuvant Treatment:Time has come, but…. • Nivo or DabTram for BRAFmu? • Efficacy is the same if lymph node disssection is not performed? • Substages…all Stage III benefit from adjuvant treatment? • Long term toxicities? • How can we deal with late referral and late access?

  6. CA209-003: A Phase 1, Open-label, Multicenter, Multidose, Dose Escalation Study of Nivolumab in Subjects With Selected Advanced or Recurrent Malignancies Melanoma OS at 5 Years of Follow-up 1.0 0.9 0.8 0.7 0.6 Overall Survival (Probability) 0.5 0.4 0.3 0.2 0.1 42.3% 0.0 34.2% Months NIVO 0 12 24 36 48 60 72 84 96 Patients at risk: 107 65 49 42 34 30 14 4 0 NIVO Minimum follow-up of 58.3 months. CI, confidence interval; NIVO, nivolumab; OS, overall survival. Adapted from Topalian SL, et al. Presented at SITC 2017, abstract P216.

  7. CA209-066: A Phase 3, Randomized, Double-Blind Study of NivolumabvsDacarbazine in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma BRAFwt: OS 1.0 0.9 0.8 0.7 0.6 70.7% Probability of survival 0.5 57.7% 0.4 0.3 46.3% 0.2 NIVO 0.1 DTIC 26.7% 0.0 0 3 6 9 12 15 18 21 24 27 30 Months Patients at risk (n) 186 171 154 143 135 111 81 30 4 0 210 NIVO 0 208 179 146 122 92 76 60 38 16 1 DTIC Adapted from Atkinson V, et al. Presented at SMR 2015. Database lock July 15, 2015. DTIC, dacarbazine; CI, confidence interval, HR, hazard ratio; NIVO, nivolumab; NR, not reached; OS, overall survival. Median follow-up was 18.5 months for NIVO and 10.9 months for DTIC (2-year OS rates are estimated)

  8. CA209-037: Phase 3 Study of Nivolumabvs Investigator’s Choice Chemotherapy in Anti-CTLA-4 Pretreated PatientsCo-primary Endpoint: Overall Survival in All Randomized Patients1,2 100 90 80 70 60 50 40 Overall survival (%) 30 39% 20 34% 10 NIVO 0 ICC Number of patients at risk 272 230 208 178 158 138 123 112 103 71 44 16 3 0 NIVO ICC 133 119 99 85 70 62 53 49 43 28 14 2 0 0 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 OS data may be jeopardized by subsequent treatments 1. Adapted from Larkin J, et al. 2017 Jul 3:JCO2016718023. doi: 10.1200/JCO.2016.71.8023.2. Weber J, et al. Presented at SMR 2016. Patients were followed for approximately 2 years. Database lock March 29, 2016. CI, confidence interval; ICC, investigator’s choice chemotherapy; HR, hazard ratio; NIVO, nivolumab; OS, overall survival. 62% in the ICC group received subsequent systemic therapy, including 40% who received anti-PD-1 therapy 40% in the NIVO group had subsequent systemic therapy

  9. CA209-037 CoprimaryEndpoint: Responses to Treatment in the Per-Protocol Objective Response Population Updated Best Overall Response per IRRCa aRECIST v1.1. bComplete response + partial response. Patients were followed for approximately 2 years. Database lock March 29, 2016. CI, confidence interval; ICC, investigator’s choice chemotherapy; IRRC, independent radiological review committee; NIVO, nivolumab; ORR, objective response rate; RECIST, response evaluation criteria in solid tumors. Adapted from Larkin J, et al. 2017 Jul 3:JCO2016718023. doi: 10.1200/JCO.2016.71.8023.

  10. CA209-067: A Phase 3, Randomized, Double-Blind Study of NivolumabMonotherapy or Nivolumab Combined With Ipilimumab Versus IpilimumabMonotherapy in Subjects With Previously Untreated Unresectable or Metastatic Melanoma Response to Treatment The Lancet Oncology, 2018 Which patients benefit from combination treatment?

  11. Metastatic MelanomaGood news, but many questions to be answered • Response criteria • Long-term OS data • Retreatment • Role of surgeon/Neoadjuvant treatments • Sequencing I-O/I-O • Sequencing I-O/other • Treatment beyond progression • Other combinations • Predictive biomarkers • Dosing • Special populations

  12. Correlation of Antitumor Activity with Select Biomarkers: Baseline, On-treatment, Modulation? When? Where? And… What about correlation of toxicity with select biomarkers? PD-L1, PD-L2 expression IFN-g signature MHC Class I & II Tumor-associated lymphocytes Gene-expression analysis Mutation load Microbiota/Diet Response kinetics

  13. Ipi + Nivo: Results Beyond First-line are Needed!CA209-218: Expanded Access Program With Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma The purpose of this EAP was to provide NIVO+IPI treatment to patients with unresectable or metastatic melanoma who may have progressed after other therapies, but who were treatment-naïve for anti-CTLA-4 and anti-PD-1 Hogg D, et al. Presented at ASCO 2017, abstract 9522.

  14. Other Important Issues: Dosing • Flat dose vs body weight dose • Infusion duration • Treatment duration Zhao X, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx235 Martín-AlgarraS, et al. Presented at ESMO 2016, abstract 3386 .

  15. The importance of Being a Complete ResponderPooled post hoc analysis for patients treated with NIVO + IPI or NIVO alone in 3 randomized studies (CM-066, CM-069, CM-067) CR 97% 100 100 88% CR 90 90 90% 80 80 80% 70 70 Non-CR 60 60 50% OS (%) PFS (%) 50 50 Non-CR 40 40 31% 42% 30 30 20 20 NIVO + IPI NIVO + IPI 19% 10 10 NIVO NIVO Patients at risk: Patients at risk: 0 0 NIVO + IPI 327 205 155 128 1 10 106 98 92 85 80 76 72 55 17 1 0 0 0 NIVO + IPI 327 392 260 240 216 210 196 187 182 174 166 160 156 95 19 2 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 51 54 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 NIVO 434 204 155 133 1 14 104 97 90 82 72 67 62 56 33 15 3 1 0 NIVO 434 386 344 308 283 258 239 224 208 197 189 177 169 137 63 28 9 2 0 Months Months CR, complete response; IPI, ipilimumab; NIVO, nivolumab; NR, not reached; OS, overall survival; PFS, progression-free survival. Adapted from Robert C, et al. Presented at ESMO 2017, abstract 1213O.

  16. Immune-related AEs, High-dose Corticosteroids… Compromise Efficacy?Pooled Analysis of CA209-067 and -069 NIVO + IPI Treatment of Patients With Unresectable Stage III or IV Melanoma: Overall Survival 100 100 90% 85% 90 90 82% All treated patients Patients with select GI irAEs High-dose CSa 80 80 75% 73% 69% 68% 82% 70 70 64% 91% 82% 60 60 Overall survival (%) Overall survival (%) 67% 75% 71% 50 50 bP < 0.0001 bP < 0.0001 bP = 0.0031 83% 55% 100 40 40 46% 72% 90 62% 80 30 30 50% 77% 70 20 20 NIVO+IPI 60 66% 10 10 Overall survival (%) 57% 50 IPI NIVO+IPI NIVO+IPI 50% 40 0 0 IPI IPI 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 24 24 27 27 30 30 33 33 36 36 39 39 30 Months Months 20 10 NIVO+IPI 72 195 407 71 188 373 65 177 341 61 169 320 59 158 294 57 154 287 54 144 273 51 139 262 49 133 254 36 105 197 29 87 169 7 28 49 1 5 7 0 0 0 IPI 44 132 357 40 122 325 34 108 289 33 99 261 29 92 234 24 82 209 24 79 190 23 70 174 20 62 158 16 52 132 12 40 104 6 16 34 0 2 4 0 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at risk Months Patients at risk Patients at risk Database lock: February 2016, minimum follow up 24 months (CheckMate 069) and September 2016, minimum follow up 28 months (CheckMate 067). aHigh-dose CS excludes patients who have received only topical steroids or systemic steroids at a dose of prednisone < 40 mg or equivalent. CI, confidence interval; HR, hazard ratio; IPI, ipilimumab; NIVO, nivolumab; NR, not reached; OS, overall survival. Adapted from Weber JS, et al. Presented at ASCO 2017, abstract 9523.

  17. Toxicity PFS OS Schadendorf D et al.J Clin Oncol. 2017 Dec

  18. Is there a Role for Treatment Beyond Progression? Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile. Long GV, et al. JAMA Oncol. 2017 Jun 29. doi: 10.1001/jamaoncol.2017.1588. Pooled analysis to evaluate the safety and potential benefit of nivolumabmonotherapy beyond RECIST v1.1-defined progression in patients with treatment-naïve advanced melanoma

  19. Immunotherapies in Combination With Radiotherapy?Abscopal effect…myth or reality? .

  20. We Must go Beyond… CM-067: Updated OS

  21. Hechaslaspreguntas…. esperamoslasrespuestas

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