Nivolumab Sustains 9-Year Survival Benefit in Resected Stage III/IV Melanoma

Final 9-year results from the phase 3 CheckMate 238 trial (NCT02388906) demonstrated that adjuvant nivolumab (Opdivo) significantly improved long-term recurrence-free survival (RFS) compared with ipilimumab (Yervoy) in patients with resected stage III or IV melanoma.

CheckMate 238 Data that Support the Findings

At a minimum follow-up of 107 months, the median duration of RFS was 61.1 months (95% CI, 42.9–89.2) with nivolumab vs 24.2 months (95% CI, 16.6–35.1) with ipilimumab. The 9-year RFS rates were 44% in the nivolumab group and 37% in the ipilimumab group (HR, 0.76; 95% CI, 0.63–0.90).

In patients with stage III melanoma, the median distant metastasis-free survival (DMFS) exceeded 9 years with nivolumab compared with 83.8 months with ipilimumab. The 9-year DMFS rates were 54% and 48%, respectively (HR, 0.81; 95% CI, 0.65–1.00). Median overall survival (OS) exceeded 9 years in both groups, with 9-year OS rates of 69% for nivolumab and 65% for ipilimumab (HR, 0.88; 95.03% CI, 0.69–1.11).

The Kaplan Meier estimates showed the 9-year survival with nivolumab of 74% vs 70% with ipilimumab (HR, 0.87; 95% CI, 0.67-1.12).

“After a minimum of 9 years of follow-up among patients with resected stage IIIB to C or stage IV melanoma, final data from the CheckMate 238 trial reinforce the benefit of nivolumab as compared with ipilimumab with respect to RFS and DMFS,” Paolo A. Ascierto, MD, from the Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy, and co-authors wrote in the paper. “These data, which confirm findings in previous reports, also showed that the RFS benefit was seen across nearly all subgroups analyzed.”

Circadian Timing of Drug Administration

A retrospective analysis evaluated whether drug administration before or after 1 pm influenced RFS or overall survival (OS). Investigators observed that OS was similar regardless of whether doses were administered before or after 1 pm in the nivolumab, ipilimumab, or pooled groups. The analysis did not confirm a major influence of early drug administration on RFS for most doses.

Subsequent Therapy

Fewer patients in the nivolumab group required subsequent systemic anticancer therapy compared with the ipilimumab group (37.3% vs 44.6%).

• Subsequent immunotherapy was administered to 26.5% of the nivolumab group and 36.9% of the ipilimumab group.
• Specific subsequent agents included pembrolizumab (Keytruda) in 7.7% of the nivolumab group vs 20.5% of the ipilimumab group, and nivolumab in 14.1% vs 18.8%, respectively.
• Other subsequent treatments included surgery (22.5% vs 19.6%), BRAF inhibitors (15.9% vs 15.7%), and radiotherapy (9.3% vs 10.6%).

Trial Details

CheckMate 238 was a phase 3, randomized, double-blind trial. Patients were randomly assigned in a 1:1 ratio to receive either intravenous nivolumab at 3 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks thereafter. Treatment continued for up to 1 year or until disease recurrence or unacceptable toxicity.

This multicenter, double-blind study was conducted to determine if the RFS benefits observed in earlier analyses were sustained over a nearly decade-long follow-up period. Investigators found that patients receiving nivolumab maintained a higher rate of RFS and DMFS than those receiving ipilimumab, supporting nivolumab as a preferred adjuvant treatment in this high-risk population.

Patient Population

The trial enrolled 906 patients, 453 in each group, between March 30 and November 30, 2015.

• Eligible patients were aged 15 years or older with histologically confirmed, completely resected stage IIIB, IIIC, or IV melanoma per AJCC 7th edition.
• All participants had an ECOG performance-status score of 0 or 1.
• Random assignment was stratified by disease stage and PD-L1 status.

Main End Points

The primary end point was RFS in the intention-to-treat population. Secondary end points included OS and safety. DMFS in stage III disease was an exploratory end point.

Safety

Safety data were previously reported up to 100 days after the last dose and have not been updated since the 4-year database lock. No new late adverse effects (AEs) or treatment-related safety concerns were reported during the extended follow-up period. At the time of the 9-year lock, investigators recorded no new investigator-assessed treatment-related AEs since the 4-year analysis.

Reference

Ascierto PA, Del Vecchio M, Merelli B, et al. Nivolumab for resected stage III or IV melanoma at 9 years. N Engl J Med. 2026;394(4):333-342. doi:10.1056/NEJMoa2504966