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Soo Park, MD
Soo Park, MD
Posted: Friday, December 12, 2025
In the final analysis from the phase III CheckMate 238 trial, which was recently published in The New England Journal of Medicine, Paolo A. Ascierto, MD, of the Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale in Naples, Italy, and colleagues reported 9-year outcomes comparing adjuvant nivolumab with ipilimumab in patients with completely resected stage IIIB, IIIC, or IV melanoma. The long-term data were needed to clarify survival durability following earlier reports showing superior recurrence-free survival with nivolumab.
Study Details
The double-blind, multicenter trial enrolled 906 participants between March and November of 2015. Patients were randomly assigned 1:1 to receive either nivolumab (at 3 mg/kg every 2 weeks, n = 453) or ipilimumab (at 10 mg/kg every 3 weeks for four doses, then every 12 weeks, n = 453), for up to 1 year or until disease recurrence or unacceptable toxicity. Randomization was stratified by disease stage and PD-L1 expression. Patients were ≥ 15 years old and had completely resected stage IIIB, IIIC, or IV melanoma. The primary endpoint of the trial was recurrence-free survival; secondary endpoints included overall survival, distant metastasis–free survival, and safety.
Key Findings
At 9 years, nivolumab continued to demonstrate a sustained advantage in recurrence-free survival, with a median of 61.1 months vs 24.2 months for ipilimumab (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.63–0.90). A total of 44% of patients in the nivolumab group remained recurrence-free at 9 years compared with 37% in the ipilimumab group. Distant metastasis–free survival among patients with stage III melanoma also favored nivolumab, with rates of 54% vs 48% at 9 years (HR = 0.81, 95% CI = 0.65–1.00). Median overall survival exceeded 9 years in both groups, with 69% of nivolumab-treated patients and 65% of ipilimumab-treated patients alive at 9 years (HR = 0.88, 95.03% CI = 0.69–1.11).
Patterns of recurrence were consistent across both study groups, with the lungs, lymph nodes, liver, and brain representing the most common sites of distant relapse. Subsequent systemic therapy was required less frequently after nivolumab (37.3%) compared with ipilimumab (44.6%), and no new late safety signals emerged. Adverse event reporting ended 100 days after treatment completion, with no additional treatment-related toxicities reported.
Overall, the final 9-year results of CheckMate 238 reaffirm nivolumab as an effective and durable adjuvant therapy for high-risk resected melanoma, offering sustained protection against recurrence and distant metastasis with a favorable long-term safety profile. Although overall survival remained similar between groups—likely due to effective postrecurrence therapies and the use of ipilimumab as an active comparator—the substantial and lasting improvement in recurrence-free outcomes continues to support nivolumab as the preferred adjuvant option in this patient population.
“The long-term outcomes from CheckMate 238 confirm that nivolumab is a proven adjuvant treatment for patients with melanoma at high risk for recurrence, with sustained improvement in recurrence-free survival and distant metastasis–free survival, as compared with ipilimumab, along with a more tolerable safety profile,” the authors concluded.
Disclosure: For full disclosures of all study authors, visit nejm.org.
The New England Journal of Medicine
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