As reported in The Lancet Oncology by Paolo A. Ascierto, MD, and colleagues, 4-year results of the CheckMate 238 trial show the continued benefit of adjuvant nivolumab vs ipilimumab in recurrence-free and metastasis-free survival in patients with resected stage IIIB–IIIC or IV melanoma, with no difference observed in overall survival.

In the previously reported primary analysis, nivolumab was associated with significantly prolonged recurrence-free survival (primary endpoint) and distant metastasis-free survival.

Paolo A. Ascierto, MD

Study Details

In the double-blind trial, 906 patients from 25 countries were randomly assigned between March and November 2015 to receive nivolumab at 3 mg/kg every 2 weeks (n = 453), or ipilimumab at 10 mg/kg every 3 weeks for four doses (n = 453) and then every 12 weeks until 1 year of treatment, disease recurrence, or unacceptable toxicity.

Outcomes at 4 Years

At database lock in January 2020, median follow-up was 51 months. Median recurrence-free survival was 52.4 months (95% confidence interval [CI] = 42.5 months–not reached) in the nivolumab group vs 24.1 months (95% CI = 16.6–35.1 months) in the ipilimumab group (hazard ratio [HR] = 0.71, 95% CI = 0.60–0.86; P =.0003). Recurrence-free survival at 4 years was 51.7% vs 41.2%.

Median distant metastasis–free survival was not reached (95% CI = 52.4 months–not reached) in the nivolumab group vs 52.9 months (95% CI = 42.4 months–not reached) in the ipilimumab group (HR = 0.79, 95% CI = 0.63–0.99). Distant metastasis–free survival at 4 years was 59.2% vs 53.3%.

At the time of overall survival analysis, 211 deaths had occurred (100 in the nivolumab group, 111 in the ipilimumab group) out of an expected 302 deaths to test for significance. Median overall survival was not reached in either group (95% CI = not reached–not reached in both groups), with a nivolumab vs ipilimumab hazard ratio of 0.87 (95% CI = 0.66–1.14; P = .31). Overall survival at 4 years was 77.9% vs 76.6%.

Late Adverse Events

Late-emergent grade 3 or 4 treatment-related adverse events were reported in three patients (1%) in the nivolumab group and seven patients (2%) in the ipilimumab group. In the nivolumab group, those events consisted of diarrhea, diabetic ketoacidosis, and pneumonitis; in the ipilimumab group, they included colitis in two patients, and diarrhea, maculopapular rash, increased lipase, bone marrow failure, immune thrombocytopenic purpura, rash, and secondary adrenocortical insufficiency in one patient each.

As previously reported, there were two treatment-related deaths in the ipilimumab group (due to marrow aplasia and colitis). No additional treatment-related deaths have been reported.

The investigators concluded, “At a minimum of 4 years’ follow-up, nivolumab demonstrated sustained recurrence-free survival benefit vs 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.”

Dr. Ascierto, of Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit thelancet.com.