According to final data from the phase 3 CheckMate 238 trial, presented during the ESMO Congress, adjuvant Nivolumab has pruduced a long-term efficacy benefit compared with Ipilimumab for the treatment of patients with resected stage IIIB to IIIC or IV melanoma.

At the november, 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 relapse-free survival (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 relapse-free survival favored the Nivolumab arm in most prespecified subgroups.

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. 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.

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 endpoint was relapse-free survival in the ITT population. Key secondary endpoints included overall survival (OS) and safety. Distant metastasis-free survival (DMFS), time to second disease progression (PFS2), and melanoma-specific survival (MSS) were exploratory endpoints.

The median distant metastasis-free survival 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). 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 overall survival in both arms was not-reached, however a benefit in favor of the Nivolumab arm was reported (HR, 0.88; 95% CI, 0.69-1.11). Similarly, the median melanoma-specific survival was not-reached in either arm, but data for this outcome favored the investigational arm (HR, 0.87; 95% CI, 0.67-1.12).

The median time to second disease progression 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.

An analysis of the efficacy and safety of adjuvant Nivolumab versus Ipilimumab based on the time of administration was performed, comparing morning with afternoon dosing. In a pooled patient population, a trend towards a 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 a 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 overall survival 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.

In conclusion, these 9-year data represent the longest follow-up of a checkpoint inhibitor in an adjuvant trial of patients with melanoma, continuing to see a better recurrence-free survival among patients treated with Nivolumab compared with the active comparator Ipilimumab. ( Xagena_2025 )

Ascierto PA et al, ESMO Congress 2025 [ Abstract 1609MO ]

XagenaMedicine_2025