Nivolumab bests ipilimumab in head-to-head melanoma trial

The final, long-term results from the phase III CheckMate 238 trial continue to show the superior recurrence-free survival (RFS) benefit of adjuvant nivolumab (NIVO) over ipilimumab (IPI) for resected stage IIIB-C or IV melanoma.

At the 9-year follow-up mark, RFS remained better with NIVO vs IPI (median 61.1 vs 24.2 months; hazard ratio [HR], 0.76). This was supported by the improved distant metastasis-free survival (DMFS) with the former vs the latter (median not reached [NR] vs 83.8 months; HR, 0.81). [ESMO 2025, abstract 1609MO]

At 108 months, RFS and DMFS rates with NIVO were 44 percent and 54 percent, respectively. The corresponding rates with IPI were 37 percent and 48 percent.

Since the 7-year analysis, there were six new recurrences (two local, two regional, two new primary melanomas) and three new deaths prior to recurrence (two with NIVO, one with IPI), noted Dr Paolo Ascierto from Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy, at ESMO 2025.

“These long-term data regarding relapses and deaths, including patients who have been off treatment for 8 years, suggest that ongoing monitoring is warranted even with the long-term benefit,” he said.

NIVO continued to show RFS benefit across most patient subgroups, including ulceration and lymph node involvement in stage III, tumour PD-L1 status, and BRAF mutation status.

Overall survival (OS) rates were high with both NIVO and IPI (69 percent and 65 percent), as were melanoma-specific survival (MSS) rates (74 percent and 70 percent), but median OS and MSS were NR with both agents (HRs, 0.88 and 0.87, respectively).

Furthermore, PFS2* outcomes suggest that adjuvant NIVO does not negatively impact subsequent systemic therapy (median NR vs 83.6 months; HR, 0.77).

Forty-five percent of participants on NIVO and 51 percent of IPI recipients had subsequent therapy. The most common systemic therapies used in the respective arms were IPI (17 percent) and pembrolizumab (21 percent).

Early dosing

There was a trend toward improved RFS with AM vs PM dosing (before vs after 1:00 PM) in the pooled cohort (median 54.7 vs 24.1 months; HR, 0.81) and IPI arm (median 30.5 vs 15.4 months; HR, 0.74) but not in the NIVO arm (median 70.4 vs 44.2 months; HR, 0.92).

According to discussant Dr Christian Blank from the Netherlands Cancer Institute, Amsterdam, Netherlands, the positive trend with IPI and the lack thereof with NIVO suggest that immune cells exposed to anti-CTLA-4, but not anti-PD-1, may be sensitive to morning exposure.

OS was similar between AM and PM dosing across the three cohorts. There were fewer grade 3/4 treatment-related adverse events with AM vs PM dosing with both NIVO (12 percent vs 21 percent) and IPI (42 percent vs 55 percent).

Ascierto called for further exploration on the effects of early dosing to validate these results.

Study details

CheckMate 238 comprised 906 patients (median age 55 years, 58 percent men) with high-risk, completely resected stage IIIB-C or IV melanoma who had not had prior systemic therapy. Participants were randomized 1:1 to IV NIVO 3 mg/kg Q2W or IPI 10 mg/kg Q3W for four doses, then Q12W from week 24 for up to a maximum of 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal.

Approximately half of the participants had stage IIIC disease, 59 percent had macroscopic lymph-node involvement in stage III, and ~57 percent did not have tumour ulceration in stage III.

Ascierto noted that the initial CheckMate 238 results paved the way for the first approval for a PD-1 inhibitor as adjuvant treatment for melanoma by the FDA and the European Commission. Subcutaneous NIVO is also FDA- and EMA-approved for adjuvant treatment of completely resected stage IIB, IIC, III, or IV melanoma, offering a treatment alternative with a quicker and more convenient route of administration.

“The 9-year data represent the longest minimum follow-up of an immune-mediated checkpoint inhibitor in any adjuvant solid tumour setting,” Ascierto said.