Background The results of phase 1 and phase 2 studies suggest that nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab combined with ipilimumab versus ipilimumab alone were evaluated in patients with metastatic melanoma. Methods We randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma, in 1:1:1 ratio, to nivolumab alone (3 mg per kilogram of body weight every 2 weeks), or to nivolumab (at a dose of 1 mg per kilogram) plus ipilimumab (at a dose of 3 mg per kilogram) every 3 weeks for 4 doses followed by nivolumab (3 mg per kilogram every 2 weeks), or to ipilimumab alone (3 mg per kilogram every 3 weeks for 4 doses). Progression-free and overall survival were co-primary end points. Patients continue to be followed for overall survival. Results Median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) for nivolumab plus ipilimumab as compared with 2.9 months (95% CI, 2.8 to 3.4) for ipilimumab alone (hazard ratio, 0.42; 95% CI, 0.31 to 0.57; P<0.00001), and was 6.9 months (95% CI, 4.3 to 9.5) for nivolumab alone (hazard ratio in the comparison with ipilimumab alone, 0.57; 95% CI, 0.43 to 0.76; P<0.00001). In PD-L1-positive patients, median progression-free survival was 14.0 months in both the nivolumab plus ipilimumab and nivolumab alone groups, but in PD-L1-negative patients, progression-free survival was longer with the combination as compared with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Grade 3–4 drug-related adverse events occurred in 16.3%, 55.0%, and 27.3% of patients in the nivolumab, nivolumab plus ipilimumab, and ipilimumab alone groups, with 1, 0, and 1 drug-related deaths, respectively. Conclusions Nivolumab alone or combined with ipilimumab significantly improved progression-free survival, as compared with ipilimumab, among previously untreated patients with metastatic melanoma. Results with the combination versus either agent alone suggest complementary activity between PD-1 and CTLA-4 blockade, particularly for patients with PD-L1-negative tumors. (Funded by Bristol-Myers Squibb; CheckMate 067, ClinicalTrials.gov number, NCT01844505.)

BACKGROUND Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)

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Summary Background Metastatic DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) colorectal cancer (mCRC) has a poor prognosis following conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all features that correspond with response to programmed cell death receptor-1 (PD-1) blockade in other tumour types. Thus, nivolumab, a PD-1 immune checkpoint inhibitor, was evaluated in this population. Methods In this is ongoing, multicentre, open-label, nonrandomised, phase 2 trial, adult patients (aged ≥18 years) with histologically confirmed recurrent or mCRC locally assessed as dMMR/MSI-H who had progressed on/after or been intolerant of at least one prior line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan, were enrolled. Patients were given nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors v1·1. All patients who received at least one dose of study drug were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02060188. Findings Among the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, most (54·1%) had received ≥3 prior therapies. At a median follow-up of 12·0 months (interquartile range 8·57–18·00 months), 23 of 74 patients (31·1% [95% CI 20·8%–42·9%]) achieved an investigator-assessed objective response; 68·9% (95% CI 57·1%–79·2%) of patients had disease control for ≥12 weeks. Median duration of response was not yet reached; all responders were alive, and 8 (34·8%) had responses of ≥12 months. The most common (≥10% of patients) drug-related adverse events was fatigue (n=16 [21·6%]), diarrhoea (n=15 [20·3%]), pruritus (n=10 [13·5%]) and rash (n=8 [10·8%]). The most common grade 3 or 4 drug-related adverse events were increased lipase (n=6 [8·1%]) and amylase (n=2 [2·7%]) levels. Five patients (6·8%) discontinued treatment because of increased alanine aminotransferase, colitis, duodenal ulcer, acute kidney injury, and stomatitis (n=1 each). Twenty-three patients (31·1%) died during the study; none of these deaths was considered to be treatment related by the investigator. Interpretation Nivolumab provided durable responses and disease control, as well as long-term survival in pre-treated patients with dMMR/MSI-H mCRC, and is a new treatment option for these patients.