@article{2655bd42920b46938ae9b0bb65495983,
title = "Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial: The Lancet Oncology",
abstract = "Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB–C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results. Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB–C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906. Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6–52·7) with nivolumab and 50·9 months (36·2–52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8–56·3) in the nivolumab group and 41·2% (36·4–45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60–0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7–81·5) with nivolumab and 76·6% (72·2–80·3) with ipilimumab (HR 0·87 [95% CI 0·66–1·14]; p=0·31). Late-emergent grade 3–4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported. Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Funding: Bristol Myers Squibb and Ono Pharmaceutical. {\textcopyright} 2020 Elsevier Ltd",
keywords = "alanine aminotransferase, amylase, aspartate aminotransferase, gamma glutamyltransferase, ipilimumab, nivolumab, triacylglycerol lipase, CTLA4 protein, human, cytotoxic T lymphocyte antigen 4, monoclonal antibody, adjuvant therapy, adrenal cortex insufficiency, adult, aged, arthralgia, arthritis, Article, autoinflammatory disease, bone marrow aplasia, bone marrow depression, cancer center, cancer recurrence, cancer staging, cancer surgery, carpal tunnel syndrome, colitis, community hospital, coughing, dermatitis, diabetic ketoacidosis, diarrhea, distant metastasis free survival, drug efficacy, drug fatality, drug safety, drug tolerability, facial nerve paralysis, fatigue, female, fever, follow up, hazard ratio, human, hyperamylasemia, hypertransaminasemia, hypophysitis, hypothyroidism, idiopathic thrombocytopenic purpura, intention to treat analysis, interactive voice response system, interstitial lung disease, lichen planus, liver toxicity, maculopapular rash, major clinical study, male, melanoma, middle aged, multicenter study (topic), multiple cycle treatment, muscle weakness, musculoskeletal stiffness, myalgia, nausea, overall survival, pemphigoid, peripheral edema, peripheral neuropathy, phase 3 clinical trial (topic), pneumonia, priority journal, pruritus, randomized controlled trial (topic), rash, recurrence free survival, sensory neuropathy, side effect, skin carcinoma, thrombocytopenia, treatment duration, treatment outcome, university hospital, vitiligo, adverse drug reaction, classification, clinical trial, controlled study, disease free survival, double blind procedure, genetics, multicenter study, pathology, phase 3 clinical trial, randomized controlled trial, tumor recurrence, Aged, Antibodies, Monoclonal, CTLA-4 Antigen, Disease-Free Survival, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Ipilimumab, Male, Melanoma, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Nivolumab, Treatment Outcome",
author = "P.A. Ascierto and {Del Vecchio}, M. and M. Mandal{\'a} and H. Gogas and A.M. Arance and S. Dalle and C.L. Cowey and M. Schenker and J.-J. Grob and V. Chiarion-Sileni and I. M{\'a}rquez-Rodas and M.O. Butler and M. Maio and M.R. Middleton and {de la Cruz-Merino}, L. and P. Arenberger and V. Atkinson and A. Hill and L.A. Fecher and M. Millward and N.I. Khushalani and P. Queirolo and M. Lobo and {de Pril}, V. and J. Loffredo and J. Larkin and J. Weber",
note = "Cited By :11 Export Date: 1 March 2021 CODEN: LOANB Correspondence Address: Ascierto, P.A.; Istituto Nazionale Tumori IRCCS Fondazione PascaleItaly; email: paolo.ascierto@gmail.com Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; amylase, 9000-90-2, 9000-92-4, 9001-19-8; aspartate aminotransferase, 9000-97-9; gamma glutamyltransferase, 85876-02-4; ipilimumab, 477202-00-9; nivolumab, 946414-94-4; triacylglycerol lipase, 9001-62-1; Antibodies, Monoclonal; CTLA-4 Antigen; CTLA4 protein, human; Ipilimumab; Nivolumab Manufacturers: Bristol Myers Squibb; Ono Funding details: Merck Sharp and Dohme, MSD Funding details: Bristol-Myers Squibb Canada, BMS Funding details: Novartis Funding details: Astellas Pharma Funding details: AbbVie Funding details: Pfizer Funding details: Eli Lilly and Company Funding details: Samsung Funding details: Roche Italia Funding details: Gilead Sciences Funding details: AstraZeneca Funding details: Clovis Oncology Funding details: Merck Funding details: Genentech Funding text 1: PAA has worked in a consulting or advisory role for Alkermes, Array BioPharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Idera Pharmaceuticals, Immunocore, Incyte, Italfarmaco, Eisai, 4SC, MedImmune, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, Sun Pharma, Syndax, and Ultimovacs; has received research or grant support from Array BioPharma, Bristol Myers Squibb, and Roche/Genentech; and has received travel support from Merck Sharp & Dohme. MDV has worked in a consulting or advisory role for and received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sanofi. MMan has worked in a consulting or advisory role for Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. HG has worked in a consulting or advisory role for Amgen, Bristol Myers Squibb, and Merck Sharp & Dohme; has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; and has received travel, accommodations, or expenses support from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Roche. AMA has worked in a consulting or advisory role for Amgen, Bristol Myers Squibb, Merck, Roche, and Sanofi; has received honoraria from Amgen, Bristol Myers Squibb, Merck, Roche, and Sanofi; has served as a speaker or provided expert testimony for Bristol Myers Squibb, Merck, and Roche; and has received travel, accommodations, or expenses support from Amgen, Bristol Myers Squibb, Merck, Roche, and Sanofi. SD has received research or grant support and congress support from Bristol Myers Squibb and Merck Sharp & Dohme. CLC has worked in a consulting or advisory role for Iovance, Merck, Novartis, Pfizer, and Regeneron; has received honoraria from Regeneron; has received research or grant support from Amgen, Array BioPharma, Bristol Myers Squibb, Celldex, Genentech, Merck, Novartis, and Regeneron; and has received travel, accommodations, or expenses support from Regeneron. MS has received research or grant support from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Clovis, Eli Lilly, Gilead, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Samsung. J-JG has worked in a consulting or advisory role for Amgen, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. VC-S has worked in a consulting or advisory role for Novartis and Pierre Fabre; has served as a speaker for Merck Serono and Merck Sharp & Dohme; and has received travel, accommodations, or expenses support from Bristol Myers Squibb and Pierre Fabre. IM-R has worked in a consulting or advisory role for AstraZeneca, Bioncotech, Bristol Myers Squibb, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and has received travel, accommodations, or expenses support from Bioncotech, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche. MOB has worked in a consulting or advisory role for Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Immunocore, Merck, Novartis, Pfizer, and Sanofi; has received research or grant support from Merck; and has served on the safety review board for Adaptimmune and GlaxoSmithKline. MMai has worked in a consulting or advisory role for Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, and Roche. MRM has worked in a consulting or advisory role for Array BioPharma, BiolineRx, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, Kineta, Merck, Merck Sharp & Dohme, Rigontec, and Silicon Therapeutics; has served on the independent data safety monitoring committee for Eisai, Merck, and Merck Sharp & Dohme; has received institutional research or grant support from Array BioPharma, BiolineRx, Bristol Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, Regeneron, Replimmune, and Rigontec; and has received travel, accommodations, or expenses support from Merck, Merck Sharp & Dohme, and Replimmune. LdlC-M has worked in a consulting or advisory role for Novartis, Pierre Fabre, and Roche; and has served as a speaker for Amgen, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, and Pfizer. VA has worked in a consulting or advisory role for Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Nektar Therapeutics, Novartis, Pierre Fabre, and Roche; has served as a speaker for Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, and Roche; and has received travel, accommodations, or expenses support from Bristol Myers Squibb and OncoSec. LAF has worked in a consulting or advisory role for Elsevier and Via Oncology; has received cooperative group research or grant support from Array BioPharma; has received institutional research or grant support from Array BioPharma, Bristol Myers Squibb, EMD Serono, Incyte, Kartos Therapeutics, Merck, Merck KGaA, Pfizer, and SU2C-MRA; and has served on the data and safety monitoring board of the Hoosier Cancer Research Network. MMi has worked in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and has received conference and travel, accommodations, or expenses support from AstraZeneca, Bristol Myers Squibb, and Roche. NIK has worked in a consulting or advisory role for Array Biopharma, Bristol Myers Squibb, EMD Serono, Genentech, Immunocore, Jounce Therapeutics, Merck, HUYA Bioscience, Regeneron, and Sanofi; has received institutional research or grant support from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, HUYA Bioscience, Merck, Novartis, and Regeneron; holds stock in Amarin, Bellicum, Mazor Robotics, and TransEnterix; and has served on the data and safety monitoring board of AstraZeneca and Incyte. PQ has worked in a consulting or advisory role for Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, Roche/Genentech, and Sanofi. ML and JLo are employees of Bristol Myers Squibb. VdP is an employee of and holds stock or stock options in Bristol Myers Squibb. JLa has worked in a consulting or advisory role for Achilles Therapeutics, AstraZeneca, Aveo, Boston Biomedical, Bristol Myers Squibb, Covance, Eisai, EUSA Pharma, GlaxoSmithKline, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck, Merck Sharp & Dohme, Nektar Therapeutics, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche, Secarna, and Vitaccess; and has received research or grant support from Achilles Therapeutics, Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Nektar Therapeutics, Novartis, Pfizer, and Roche. JW has worked in a consulting or advisory role for, received honoraria from, and received institutional research or grant support from Bristol Myers Squibb; and is named on a patent for a PD-1 biomarker not used in the current trial. PA and AH declare no competing interests. Funding text 2: Funding for the study was provided by Bristol Myers Squibb and Ono Pharmaceutical. We thank the patients and investigators who participated in the CheckMate 238 trial. We also acknowledge Ono Pharmaceutical for contributions to nivolumab development and Dako for the collaborative development of the PD-L1 immunohistochemistry 28-8 pharmDx assay. Professional medical writing and editorial assistance were provided by Melissa Kirk and Michele Salernitano at Ashfield Healthcare Communications, funded by Bristol Myers Squibb. 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year = "2020",
doi = "10.1016/S1470-2045(20)30494-0",
language = "English",
volume = "21",
pages = "1465--1477",
journal = "Lancet Oncol.",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "11",
}