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.

Center for Immuno Oncology University Hospital of Siena Siena Italy

Clinical Biomarkers Bristol Myers Squibb Princeton NJ USA

Department of Clinical Oncology Hospital University Virgen Macarena Seville Spain

Department of Cutaneous Oncology H Lee Moffitt Cancer Center Tampa FL USA

Department of Dermatology Aix Marseille University Hôpital de la Timone Marseille France

Department of Dermatology Charles University 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Global Regulatory and Safety Sciences Bristol Myers Squibb Princeton NJ USA

Department of Immuno oncology Princess Margaret Cancer Centre Toronto ON Canada

Department of Internal Medicine University of Western Australia and Sir Charles Gairdner Hospital Nedlands WA Australia

Department of Medical Oncology General University Hospital Gregorio Marañón and CIBERONC Madrid Spain

Department of Medical Oncology Internal Medicine University of Michigan Rogel Cancer Center Ann Arbor MI USA

Department of Medical Oncology Tasman Health Care Southport QLD Australia

Department of Medical Oncology The Royal Marsden NHS Foundation Trust London UK

Department of Oncology Churchill Hospital Oxford UK

Division of Cancer Services Gallipoli Medical Research Foundation University of Queensland Brisbane QLD Australia

Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Hospices Civils de Lyon Pierre Bénite France

Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

IEO European Institute of Oncology IRCCS Milan Italy

Istituto Nazionale Tumori IRCCS Fondazione Pascale Naples Italy

Laura and Isaac Perlmutter Cancer Center NYU Langone Health New York NY USA

National and Kapodistrian University of Athens Athens Greece

Oncology Center Sf Nectarie Craiova Romania

Oncology Clinical Development Bristol Myers Squibb Princeton NJ USA

Papa Giovanni XIII Hospital Bergamo Italy

Texas Oncology Baylor Charles A Sammons Cancer Center Dallas TX USA

Veneto Institute of Oncology IOV IRCCS Padua Italy

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