Recurrence-Free Survival Benefit Maintained With Adjuvant Nivolumab vs Ipilimumab in Stage IIIB–IIIC and IV Melanoma

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As reported in The Lancet Oncology by Paolo A. Ascierto, MD, of the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, and colleagues, 4-year results of the CheckMate 238 trial show continued benefit of adjuvant nivolumab vs ipilimumab in recurrence-free survival and metastasis-free survival in patients with resected stage IIIB–IIIC or stage IV melanoma, with no difference observed in analysis of overall survival.1

Paolo A. Ascierto, MD

Paolo A. Ascierto, MD

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

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.

In the primary analysis, with a median follow-up of 19.5 months, recurrence-free survival at 1 year was 70.5% in the nivolumab group vs 60.8% in the ipilimumab group (hazard ratio [HR] = 0.65, P < .001); 3-year recurrence-free survival was subsequently reported at 58% vs 45%. Nivolumab was associated with reduced toxicity, with treatment-related grade 3 or 4 adverse events being reported in 14.4% vs 45.9% of patients, and treatment-related adverse events leading to treatment discontinuation in 7.7% vs 41.7%.

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 to not reached) in the nivolumab group vs 24.1 months (95% CI = 16.6–35.1 months) in the ipilimumab group (HR = 0.71, 95% CI = 0.60–0.86; P = .0003). Recurrence-free survival at 4 years was 51.7% vs 41.2%.

In recurrence-free survival subgroup analyses, hazard ratios by disease stage were 0.70 (95% CI = 0.50–0.98) among 165 vs 147 patients with stage IIIB disease, 0.74 (95% CI = 0.57–0.96) among 203 vs 219 with stage IIIC disease, 0.65 (95% CI = 0.41–1.03) among 62 vs 66 with stage IV M1a-M1b disease, and 1.13 (95% CI = 0.44–2.93) among 20 vs 21 with stage IV M1c disease. By PD-L1 status, hazard ratios were 0.74 (95% CI = 0.59–0.91) among 300 vs 299 patients with less than 5% positive tumor cells or indeterminate status and 0.67 (95% CI = 0.47–0.96) among 153 vs 154 with at least 5% positive cells. By BRAF mutation status, hazard ratios were 0.79 (95% CI = 0.60–1.05) among 187 vs 194 patients with BRAF mutation, 0.69 (95% CI = 0.53–0.91) among 197 vs 212 with wild-type BRAF, and 0.66 (95% CI = 0.38–1.12) among 69 vs 47 with no reported BRAF status.

Distant metastasis was the most common site of recurrence, occurring in 122 patients in the nivolumab group vs 146 in the ipilimumab group, followed by local recurrence in 37 vs 48 patients and regional recurrence in 38 vs 41 patients. A new primary melanoma occurred in 11 vs 7 patients.

Median distant metastasis–free survival was not reached (95% CI = 52.4 months to not reached) in the nivolumab group vs 52.9 months (95% CI = 42.4 months to 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%.

In distant metastasis–free survival subgroup analyses, hazard ratios were 0.78 (95% CI = 0.54–1.14) among patients with stage IIIB disease and 0.82 (95% CI = 0.62–1.09) among those with stage IIIC disease. By PD-L1 status, hazard ratios were 0.80 (95% CI = 0.61–1.04) among patients with less than 5% positive tumor cells or indeterminate status and 0.79 (95% CI = 0.51–1.22) among those with at least 5% positive cells. By known BRAF mutation status, hazard ratios were 0.82 (95% CI = 0.57–1.16) among patients with BRAF mutation and 0.79 (95% CI = 0.57–1.09) among those with wild-type BRAF.


  • At 4 years, nivolumab maintained a significant recurrence-free survival benefit over ipilimumab.
  • No difference in overall survival has been observed.

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. Median overall survival was not reached in either group (95% CI = not reached to 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%.

Subsequent postprotocol anticancer therapy was received by 41% of the nivolumab group vs 49% of the ipilimumab group, including surgery in 20% vs 18%, radiation therapy in 8% vs 10%, and systemic therapy in 33% vs 42%, with 8% vs 9% receiving chemotherapy and 23% vs 34% receiving immunotherapy.

Late Adverse Events

Late-emergent grade 3 or 4 treatment-related adverse events were reported in three patients (1%) in the nivolumab group and in seven patients (2%) in the ipilimumab group. In the nivolumab group, these events consisted of diarrhea, diabetic ketoacidosis, and pneumonitis; in the ipilimumab group, they consisted of 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.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. Dr. Ascierto holds stock or other ownership interests in PrimeVax; has served as a consultant or advisor to 4SC, Alkermes, Array BioPharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Idera, Immunocore, Incyte, Italfarmaco, MedImmune, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Regeneron, Roche/Genentech, Sandoz, Sanofi, Sun Pharma, and Ultimovacs; has received institutional research funding from Array BioPharma, Bristol Myers Squibb, and Roche/Genentech; and has been reimbursed for travel, accommodations, or other expenses by Merck Sharp & Dohme.


1. Ascierto PA, Del Vecchio M, Mandalá M, et al: Adjuvant nivolumab vs ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase III trial. Lancet Oncol. September 18, 2020 (early online release).