SUMMARY: The American Cancer Society estimates that in the US, approximately 112,000 new cases of melanoma will be diagnosed in 2026 and about 8510 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades.
Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease specific survival rates of 59% and 40% respectively.
Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these membrane bound, inhibitory, immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc., block the immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.
Ipilimumab (YERVOY®) was approved by the FDA for the adjuvant treatment of patients with completely resected Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized Phase III trial. In this study however, over 50% of the patients treated with the recommended high dose Ipilimumab experienced Grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.
Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with Nivolumab, in heavily pretreated advanced melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment.
Study Details
CheckMate 238 trial is a double-blind Phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either Nivolumab 3 mg/kg IV, every 2 weeks (N=453) or Ipilimumab 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. Patients were stratified according to disease stage and PD-L1 status (positive vs. negative or indeterminate according to tumor-cell PD-L1 expression with a 5% cutoff). The Primary end point was Recurrence Free Survival (RFS).
Data from the primary analysis showed that adjuvant Nivolumab was superior to Ipilimumab with respect to RFS and Distant Metastasis–Free Survival (DMFS), and had a more favorable safety profile. This benefit was seen regardless of BRAF mutational status with Nivolumab, and was sustained at a minimum follow-up of up to 7 years. The Overall Survival at 4 years and 7 years was 71% with Nivolumab and 69% with Ipilimumab, and was not significantly different.
In this publication, the researchers provided the final results from CheckMate 238, with a minimum follow-up of 9 years (107 months).
Efficacy at 9 Year Follow-up
The median duration of RFS was 61.1 months with Nivolumab and 24.2 months with Ipilimumab (HR for recurrence or death=0.76) and the 9-year RFS was 44% and 37%, respectively. This benefit was seen across nearly all subgroups analyzed.
The median duration of DMFS in Stage III melanoma patients was more than 9 years with Nivolumab and 83.8 months with Ipilimumab, with 9-year survival of 54% and 48%, respectively (HR for distant metastasis or death=0.81).
The median OS was more than 9 years in both treatment groups, with 9-year survival of 69% in the Nivolumab group and 65% in the Ipilimumab group (HR for death=0.88). The rates of death from melanoma at 9 years were 26% with Nivolumab and 30% with Ipilimumab (HR=0.87; 95% CI, 0.67 to 1.13). It is still uncertain whether OS is improved when treatment is administered in the adjuvant setting compared with initiation at the time of metastatic disease. These outcomes indicate that, similar to trends in metastatic therapy, many patients receiving adjuvant treatment now live long enough to succumb to causes unrelated to melanoma.
Fewer patients in the Nivolumab group required subsequent systemic therapy compared to those in the Ipilimumab group (37.3% vs. 44.6%), with no new late-onset adverse events reported.
Conclusion
Final 9-year data from the CheckMate 238 trial confirms that adjuvant Nivolumab provides sustained improvements in Recurrence-Free Survival (RFS) and Distant Metastasis–Free Survival compared to Ipilimumab, in high-risk melanoma patients, maintaining a safer profile. The results highlight the need for ongoing long-term monitoring.
Nivolumab for Resected Stage III or IV Melanoma at 9 Years. Ascierto PA, Vecchio MD, Merelli B, et al. N Engl J Med 2026;394:333-342
