Among patients with resected stage 3B to 4 melanoma, postsurgical treatment with Opdivo (nivolumab) was associated with a long-term efficacy benefit compared with Yervoy (ipilimumab), clinical trial results have shown.
Final data from the phase 3 CheckMate 238 trial were presented during the 2025 ESMO Congress and published in The New England Journal of Medicine.
At the Nov. 12, 2024, data cutoff, at a minimum follow-up of 107 months, patients who received adjuvant Opdivo (453 patients) achieved a median relapse-free survival (RFS) of 61.1 months compared with 24.2 months among those treated with Yervoy (453 patients). The 60-, 84- and 108-month RFS rates in the Opdivo arm were 51%, 46% and 44%, respectively. These respective rates were 39%, 38% and 37% in the Yervoy arm. The median RFS favored the Opdivo arm in most prespecified subgroups.
“These nine-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 [Opdivo] compared with the active comparator Yervoy,” Dr. Paolo A. Ascierto, 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 3B, 3C or 4 melanoma. 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 and PD-L1 status at a 5% cutoff.
Eligible patients were randomly assigned to receive intravenous Opdivo at 3 mg/kg every two weeks or Yervoy at 10 mg/kg every three weeks for four doses and every 12 weeks subsequently. Treatment continued for one 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 Opdivo (370 patients) and Yervoy (366 patients) arms was not reached and 83.8 months, respectively. The 60-, 84- and 108-month DMFS rates in the Opdivo arm were 59%, 55% and 54%, respectively. These respective rates in the Yervoy arm were 52%, 50% and 48%.
The median OS in both arms was not reached, however a benefit in favor of the Opdivo arm was reported. Similarly, the median MSS was not reached in either arm, but data for this outcome favored the investigational arm.
The median PFS2 in the Opdivo arm (453 patients) was not reached compared with 83.6 months in the Yervoy arm (453 patients). The 60-, 84- and 108-month PFS2 rates were 64%, 58% and 55% in the Opdivo arm. In the Yervoy arm, these respective rates were 54%, 49% and 47%. PFS2 outcomes suggest that adjuvant treatment with Opdivo does not negatively affect subsequent systemic therapy, Ascierto noted.
The study authors also performed an analysis of the efficacy and safety of adjuvant Opdivo versus Yervoy 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 Yervoy (HR, 0.74; 95% CI, 0.52-1.06). There was no difference in OS with morning vs afternoon dosing in the Opdivo, Yervoy 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 Opdivo and Yervoy groups. In the Opdivo arm, patients who received morning (171 patients) or afternoon (105 patients) dosing experienced any-grade treatment-related side effects at respective rates of 82% and 91%; grade 3 (severe) or 4 (life-threatening) treatment-related side effects were reported at rates of 12% and 21% during the respective time frames. Similarly, patients who received Yervoy in the morning or afternoon experienced any-grade treatment-related side effects at respective rates of 95% and 96%, as well as grade 3 to 4 treatment-related side effects at rates of 42% and 55%, respectively.
“The DMFS and PFS [data] are in favor of [Opdivo], 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.”
Reference:
- “Final, 9-year results from the CheckMate 238 phase III trial of adjuvant nivolumab vs ipilimumab in resected stage IIIB–C or IV melanoma” by Dr. Paolo A. Ascierto et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1609MO.
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