Adjuvant Nivolumab Improves Long-Term RFS vs Ipilimumab in Resected Melanoma

Nine-year final results from the CheckMate 238 trial demonstrated that adjuvant nivolumab significantly improved time to second disease progression.

According to a 9-year analysis from the phase 3 CheckMate 238 (NCT02388906) trial, adjuvant nivolumab (Opdivo) showed a long-term efficacy advantage vs ipilimumab (Yervoy) in patients with resected stage IIIB to IIIC or IV melanoma, with benefits observed across multiple endpoints. These results were shared at the 2025 European Society of Medical Oncology Congress and simultaneously published in The New England Journal of Medicine.1,2

At the November 12, 2024, data cutoff, at a minimum follow-up of 107 months, patients who received adjuvant nivolumab (n = 453) achieved a median relapse-free survival (RFS) of 61.1 months (95% CI, 42.9-89.2) compared with 24.2 months (95% CI, 16.6-35.1) among those treated with ipilimumab (n = 453; HR, 0.76; 95% CI, 0.63-0.90). The 60-, 84-, and 108-month RFS rates in the nivolumab arm were 51%, 46%, and 44%, respectively. These respective rates were 39%, 38%, and 37% in the ipilimumab arm. The median RFS favored the nivolumab arm in most prespecified subgroups.

“These 9-year data represent the longest follow-up of a checkpoint inhibitor in an adjuvant trial [of patients with melanoma], and we continue to see a better RFS [among] patients treated with nivolumab compared with the active comparator ipilimumab,” Paolo A. Ascierto, MD, a full professor of Oncology at University of Napoli Federico II, as well as the director of the Department of Melanoma, Cancer Immunotherapy and Development Therapeutics at Istituto Nazionale Tumori IRCCS Fondazione Pascale in Napoli, Italy, said during the presentation.

What Were the Key Design Features of CheckMate 238?

CheckMate 238 was a multicenter, double-blind, randomized trial that enrolled patients who were at least 15 years old with histologically confirmed, completely resected stage IIIB, IIIC, or IV melanoma.2 Patients needed to have not received prior systemic therapy and have an ECOG performance status of 0 to 1 to be eligible. Patients were stratified by disease stage (IIIB-IIIC vs IV M1a or M1b vs IV M1c) and PD-L1 status at a 5% cutoff.1,2

Eligible patients were randomly assigned 1:1 to receive intravenous nivolumab at 3 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for 4 doses and every 12 weeks subsequently. Treatment continued for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal. Notably, at each dose, patients received a corresponding matched placebo infusion.

The primary end point was RFS in the ITT population. Key secondary end points included overall survival (OS) and safety. Distant metastasis-free survival (DMFS), time to second disease progression (PFS2), and melanoma-specific survival (MSS) were exploratory end points.

What Were the Additional Long-Term Efficacy Data and Safety Findings From CheckMate 238?

Additional findings from CheckMate 238 revealed that the median DMFS in the nivolumab (n = 370) and ipilimumab (n = 366) arms was not reached (NR; 95% CI, 77.1 months-NR) and 83.8 months (95% CI, 44.9-NR), respectively (HR, 0.81; 95% CI, 0.65-1.00).1 The 60-, 84-, and 108-month DMFS rates in the nivolumab arm were 59%, 55%, and 54%, respectively. These respective rates in the ipilimumab arm were 52%, 50%, and 48%.

The median OS in both arms was NR, however a benefit in favor of the nivolumab arm was reported (HR, 0.88; 95% CI, 0.69-1.11). Similarly, the median MSS was NR in either arm, but data for this outcome favored the investigational arm (HR, 0.87; 95% CI, 0.67-1.12).

The median PFS2 in the nivolumab arm (n = 453) was NR (95% CI, 107.5 months-NR) compared with 83.6 months (95% CI, 56.0-NR) in the ipilimumab arm (n = 453; HR, 0.77; 95% CI, 0.63-0.93). The 60-, 84-, and 108-month PFS2 rates were 64%, 58%, and 55% in the nivolumab arm. In the ipilimumab arm, these respective rates were 54%, 49%, and 47%. PFS2 outcomes suggest that adjuvant treatment with nivolumab does not negatively affect subsequent systemic therapy, Ascierto noted.

The study authors also performed an analysis of the efficacy and safety of adjuvant nivolumab vs ipilimumab based on the time of administration, comparing morning with afternoon dosing. In a pooled patient population, a trend towards an RFS benefit was observed among those treated with morning (n = 280) vs afternoon (n = 277) dosing (HR, 0.81; 95% CI, 0.63-1.04). A trend towards an RFS benefit was also seen with morning (n = 109) vs afternoon (n = 172) dosing with ipilimumab (HR, 0.74; 95% CI, 0.52-1.06). There was no difference in OS with morning vs afternoon dosing in the nivolumab, ipilimumab, or pooled cohorts.

In terms of safety, there was a trend toward a lower frequency of treatment-related adverse effects (TRAEs) with morning vs afternoon dosing in the nivolumab and ipilimumab groups. In the nivolumab arm, patients who received morning (n = 171) or afternoon (n = 105) dosing experienced any-grade TRAEs at respective rates of 82% and 91%; grade 3 or 4 TRAEs were reported at rates of 12% and 21% during the respective time frames. Similarly, patients who received ipilimumab in the morning or afternoon experienced any-grade TRAEs at respective rates of 95% and 96%, as well as grade 3 to 4 TRAEs at rates of 42% and 55%, respectively.

“The DMFS and PFS [data] are in favor of nivolumab, providing additional evidence to support the treatment benefit,” Ascierto said. “A post-hoc analysis on the time of infusion shows a difference in terms of RFS and safety with early dosing. [Although] this was not statistically significant, [it] deserves further exploration.”

Disclosures: Ascierto reported holding consultant/advisory roles with Anaveon, Bayer, Bio-Al Health, BioNTech, Boehringer-Ingelheim, Bristol Myers Squibb, Erasca, Genmab, ImCheck Therapeutics, Immunocore, Incyte, Italfarmaco, Lunaphore, Medicenna, Menarini, Merck Serono, Merck Sharp & Dohme, Nouscom, Novartis, Pfizer, Philogen, Pierre-Fabre, Regeneron, Replimune, Roche-Genentech, Sun Pharma, and ValoTx; receiving research funding from Bristol Myers Squibb, Medicenna, Pfizer, Regeneron, and Roche-Genentech; and receiving travel support from Pfizer, Bio-Al Health, Replimune, MSD, Pierre Fabre, and Philogen.

References

1. Ascierto PA, Del Vecchio M, Merelli B, et al. Final, 9-year results from the CheckMate 238 phase III trial of adjuvant nivolumab vs ipilimumab in resected stage IIIB–C or IV melanoma. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1609MO.
2. Ascierto PA, Del Vecchio M, Merelli B, et al. Nivolumab for resected stage III or IV melanoma at 9 Years. N Engl J Med. Published online October 18, 2025. doi:10.1056/NEJMoa2504966