Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218)

Abstract

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Trial registration: ClinicalTrials.gov NCT02186249.

Conflict of interest statement

F.S.H.: research funding: Bristol Myers Squibb (Inst), Novartis; consulting or advisory role: 7 Hills Pharma, Aduro, Apricity, Bayer, Bicara, Compass Therapeutics, Genentech/Roche, Kairos, Partners Therapeutics, Pfizer, Pionyr, Psioxus, Therapeutics Rheos, Sanofi, Surface, Takeda, Torque, Verastem; stock ownership: Pionyr, Torque. P.B.C.: research funding: NCI/Core Grant P30 CA008748, Pfizer; consulting or advisory role: Cell Medica, Merck, Scancell. M.S.: consulting or advisory role: Abbvie, Adaptimmune, Agonox, Allakos, Almac, Anaeropharma, Arbutus, Array, AstraZeneca/Medimmune, Bristol Myers Squibb, Baxalta-Shire, Biodesix, Celldex, Chugai-Roche, Genentech-Roche, Genmab, Genocea, GI Innovation, Gritstone, Hinge, Immunocore, Incyte, Innate Pharma, Inovio, Janssen/Johnson & Johnson, Kyowa-Kirin, Lilly, Lion Biotechnologies (Iovance), Merck USA, Modulate Therapeutics, Molecular Partners, Nektar, Newlink Genetics, Novartis, Omniox, Pfizer, Pieris, Pierre-Fabre, Seattle Genetics, Symphogen, Theravance, Torque, Vaccinex; stock ownership: Actym, Adaptive Biotechnologies, Amphivena, Intensity, Torque. C.D.L.: consulting or advisory role: Immunocore; research funding: Bristol Myers Squibb, Dynavax, Genentech, Immunocore, Merck, Novartis; travel expenses: Bristol Myers Squibb. R.G.: consulting or advisory role: Amgen, Array, Bristol Myers Squibb, GlaxoSmithKline, Genentech-Roche, Incyte, NewLink Genetics, Novartis; research funding: Amgen, Array, Bristol Myers Squibb, Boston Biomedical, Checkmate Pharmaceuticals, GlaxoSmithKline, Genentech-Roche, Incyte, Merck, Nektar, NewLink Genetics, Novartis, Syndax, Takeda, Tesaro. M.S.: honoraria: Bristol Myers Squibb, Merck, Novartis, Sanofi Genzyme. R.K.: consulting or advisory role: Bristol Myers Squibb, Array, Novartis, Immunocore; research funding: Merck, Regeneron. W.S.: consulting or advisory role: Bristol Myers Squibb, Merck, Novartis, Iovance, Regeneron; research funding: Bristol Myers Squibb, Merck, Novartis. M.A.: consulting or advisory role: Acceleron Pharma, Aduro Biotech, Agenus, Array BioPharma, Arrowhead Pharmaceuticals, Boehringer, Ingelheim, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Glactone Pharma, Immunocore, Iovance Biotherapeutics, Merck, Newlink Genetics/Pharmatech, Novartis, Oncolys BioPharma, Pfizer, Surface, Werewolf Pharma, X4 Pharma; research funding: Bristol Myers Squibb (Inst); honoraria: Bristol Myers Squibb. D.R.S.: grants and/or other financial support from Abbvie, Acerta Pharma, Aeglea Biotherapeutics, Amgen, ARMO BioSciences, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Evelo Therapeutics, Foundation Medicine, G1 Therapeutics, Genentech/Roche, Genzyme, GlaxoSmithKline, GRAIL, Illumina, Intuitive Surgical, Ipsen, Lilly, Merck, Millennium, Moderna Therapeutics, Nektar, Neon Therapeutics, Novartis, Oncogenex, Pfizer, PharmaMar, Precision Oncology, Purdue Pharma, Spectrum Pharmaceuticals, Sysmex, Takeda, Tesaro, Transgene, TRM Oncology, University of Texas Southwestern Medical Center – Simmons Cancer Center. A.P.: consulting or advisory role: Array, Bristol Myers Squibb, Regeneron, Seattle Genetics; research funding: Regeneron (Inst), Bristol Myers Squibb (Inst), Merck (Inst). J.M.: consulting or advisory role: Bristol Myers Squibb, Celgene, EMD Serono, Merck, Novartis, Roche; research funding: Merck. K.B.K.: consulting or advisory role: Array BioPharma, Bristol Myers Squibb, Genentech, Novartis, Seattle Genetics, Astellas; research funding: Bristol Myers Squibb (Inst); honoraria: Bristol Myers Squibb, Merck, Novartis, Seattle Genetics, Astellas, Array BioPharma, Genentech. S.E.: consulting or advisory role: Bristol Myers Squibb Canada, EMD Serono, Genzyme Canada, Merck Canada, Novartis. N.I.K.: research funding: Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, HUYA Bioscience International, Merck, Novartis, Regeneron; consulting or advisory role: Array BioPharma, AstraZeneca, Bristol Myers Squibb, EMD Serono, HUYA Bioscience International, Genentech, Immunocore, Merck, Regeneron; stock ownership: Bellicum Pharmaceuticals, Mazor Robotics, TransEnterix; Honoraria: Bristol Myers Squibb. W.v.D.: employee: Bristol Myers Squibb. M.L.: stock ownership: Bristol Myers Squibb; employee: Bristol Myers Squibb. D.H.: research funding: EMD Serono; consulting or advisory role: Amgen, Bristol Myers Squibb, EMD Serono, Merck, Novartis, Roche. For the remaining authors, there are no conflicts of interest.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Fig. 1

Patient disposition. Part 1 was the induction phase with nivolumab plus ipilimumab; part 2 was the maintenance phase with nivolumab monotherapy. aAfter the EAP end, still being followed for adverse events. EAP, expanded access program.

Fig. 2

Survival outcomes in the overall population. Kaplan–Meier curves are shown for the overall population (190 events/754 patients) with a median OS not available (minimum follow-up not reached). OS, overall survival.

Fig. 3

OS outcomes in key subgroups. Kaplan–Meier curves are shown by age, with a median OS of NR for patients aged ULN (93 events/239 patients), and 11.6 (95% CI 8.0–NR) for >2 × ULN (38 events/72 patients) (e); by BRAF status, with a median OS of NR for mutant BRAF status (84 events/329 patients) and NR for wild-type BRAF status (75 events/321 patients) (f); by M stage, with a median OS of NR for M0/M1A/M1B disease (64 events/321 patients) and NR for M1C disease (113 events/392 patients) (g); and by melanoma subtype, with a median OS of NR for cutaneous melanoma (142 events/590 patients), NR (95% CI 14.9–NR) for mucosal melanoma (17 events/47 patients), and 14.5 (95% CI 8.9–NR) for uveal melanoma (16 events/38 patients) (h). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; NR, not reached; OS, overall survival; ULN, upper limit of normal.