Introduction: The Evolution of Adjuvant Therapy in Melanoma
For decades, the management of resected Stage III and IV melanoma was characterized by limited therapeutic options and poor long-term prognoses. Before the advent of modern immunotherapy, adjuvant interferon-alpha was the primary systemic option, offering modest benefits at the cost of significant toxicity. The landscape shifted dramatically with the introduction of immune checkpoint inhibitors. The CheckMate 238 trial was a landmark study that compared nivolumab, a programmed cell death 1 (PD-1) inhibitor, against ipilimumab, a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor. While early reports established nivolumab’s superiority in recurrence-free survival, the oncology community has long awaited the final 9-year data to understand the durability of these responses and the impact on overall survival in a curative-intent setting.
Study Design and Methodology
CheckMate 238 was a randomized, double-blind, phase 3 trial that enrolled patients aged 15 years or older with completely resected Stage IIIB, IIIC, or IV melanoma. A total of 906 patients were randomly assigned in a 1:1 ratio to receive either nivolumab (3 mg/kg every 2 weeks) or ipilimumab (10 mg/kg every 3 weeks for four doses, then every 12 weeks). Treatment continued for up to 1 year, or until disease recurrence or unacceptable toxicity occurred.
Randomization was stratified by disease stage (Stage IIIB/C vs. Stage IV) and programmed cell death ligand 1 (PD-L1) expression status (at a 5% expression threshold). The primary endpoint was recurrence-free survival (RFS), defined as the time from randomization to the first recurrence, a new primary melanoma, or death from any cause. Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. The 9-year analysis represents the final planned assessment of these outcomes, providing one of the longest follow-up periods for adjuvant PD-1 therapy to date.
9-Year Recurrence-Free Survival: A Sustained Benefit
At a minimum follow-up of 107 months (nearly 9 years), nivolumab continued to demonstrate a significant and clinically meaningful improvement in RFS compared to ipilimumab. The median RFS was 61.1 months in the nivolumab group, more than double the 24.2 months observed in the ipilimumab group. The hazard ratio (HR) for recurrence or death was 0.76 (95% CI, 0.63 to 0.90), indicating a 24% reduction in the risk of recurrence with nivolumab.
Perhaps more striking is the 9-year RFS rate: 44% for patients treated with nivolumab compared to 37% for those treated with ipilimumab. These data suggest that a substantial proportion of patients who remain recurrence-free at the 5-year mark continue to maintain their disease-free status at 9 years, hinting at a potential cure for nearly half of the treated population in the nivolumab arm.
Distant Metastasis-Free and Overall Survival
In patients with Stage III melanoma, DMFS is a critical surrogate for long-term outcomes. The 9-year analysis showed a median DMFS of more than 107 months for the nivolumab group, compared to 83.8 months for the ipilimumab group (HR 0.81; 95% CI, 0.65 to 1.00). The 9-year DMFS rates were 54% and 48%, respectively. This sustained benefit in preventing distant spread is essential, as distant recurrence in melanoma often carries a much graver prognosis.
Regarding overall survival, the median OS was not reached in either group at the 9-year mark. The 9-year OS rates were 69% for nivolumab and 65% for ipilimumab (HR 0.88; 95.03% CI, 0.69 to 1.11). While the hazard ratio trended in favor of nivolumab, it did not reach statistical significance. Researchers attribute this lack of a significant OS difference to the high rate of subsequent life-prolonging therapies. In the ipilimumab group, 44.6% of patients received subsequent systemic therapy compared to 37.3% in the nivolumab group. Many patients in the ipilimumab arm received PD-1 inhibitors upon recurrence, which likely masked the potential OS benefit of frontline adjuvant nivolumab.
Safety and Long-Term Tolerability
One of the primary advantages of nivolumab over ipilimumab at the dose used in this trial (10 mg/kg) is its toxicity profile. The final analysis confirmed that no new late-onset adverse events occurred during the extended follow-up period. The safety profile remained consistent with previous reports, where nivolumab was associated with significantly fewer grade 3 or 4 treatment-related adverse events compared to high-dose ipilimumab. This long-term safety data is reassuring for clinicians prescribing adjuvant therapy to patients who are technically disease-free but at high risk of recurrence.
Expert Commentary and Clinical Implications
The CheckMate 238 9-year data provide a definitive look at the role of PD-1 inhibition in the adjuvant setting. The plateauing of the RFS and DMFS curves after the first few years suggests that adjuvant immunotherapy can fundamentally change the natural history of high-risk melanoma.
Experts note that while the OS data did not show a statistically significant difference, the RFS benefit is the most relevant metric for adjuvant therapy. Preventing a recurrence avoids the psychological burden of disease return, the physical toll of metastatic disease, and the need for more intensive salvage therapies. Furthermore, the fact that fewer patients in the nivolumab arm required subsequent systemic therapy (37.3% vs 44.6%) underscores the efficiency of early intervention with PD-1 inhibitors.
However, limitations remain. The trial used a 10 mg/kg dose of ipilimumab, which is higher than the currently standard 3 mg/kg dose used in metastatic settings, making the toxicity comparison specific to this high-dose regimen. Additionally, since the trial’s inception, newer combinations (such as nivolumab plus relatlimab or nivolumab plus ipilimumab) have emerged, raising questions about whether even better long-term RFS could be achieved with combination adjuvant therapy for certain high-risk subgroups.
Conclusion
The 9-year final results of CheckMate 238 solidify nivolumab’s position as a cornerstone of adjuvant therapy for resected Stage III and IV melanoma. With a 44% RFS rate at nearly a decade of follow-up, nivolumab offers a durable, long-term benefit that was previously unthinkable in this patient population. These findings support the continued use of nivolumab to reduce the risk of recurrence and distant metastasis, providing patients with a significant chance at long-term survival.
Funding and Clinical Trial Information
This study was funded by Bristol Myers Squibb and Ono Pharmaceutical. ClinicalTrials.gov number: NCT02388906. Eudra-CT number: 2014-002351-26.
References
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2. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824-1835.
3. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789-1801.
