Long-term findings from the phase III CheckMate 238 study showed that nivolumab improved 4-year recurrence-free survival compared with ipilimumab in patients with resected stage IIIB to C or IV melanoma in the overall population as well as across subgroups of patients stratified by disease stage and PD-L1 expression levels. The findings were presented by Jeffrey Weber, MD, PhD, at the ESMO Virtual Congress 2020 (Abstract 1076O).

Dr. Weber cited previous findings from this study, demonstrating that adjuvant nivolumab improved recurrence-free survival over ipilimumab. At ESMO 2020, he presented updated 48-month recurrence-free survival, distant metastasis–free survival, and primary overall survival results from a comparison of nivolumab vs ipilimumab in patients with resected stage IIIB to C or IV melanoma who participated in the phase III CheckMate 238 study.

Jeffrey Weber, MD, PhD

CheckMate 238

The study enrolled patients aged ≥ 15 with completely resected stage IIIB to C or IV melanoma who were stratified by disease stage and tumor PD-L1 status. The patients were randomly assigned 1:1 to receive nivolumab at 3 mg/kg every 2 weeks (n = 453) or ipilimumab at 10 mg/kg every 3 weeks for four doses and every 12 weeks thereafter (n = 453). Treatment was administered for up to 1 year or until disease recurrence or unacceptable toxicity.

The primary endpoint of CheckMate 238 was recurrence-free survival; key secondary endpoints included overall survival and safety, whereas distant metastasis–free survival in stage III disease was a key exploratory endpoint.

Updated Results

With 48 months of follow-up, nivolumab continued to demonstrate superior recurrence-free survival compared with ipilimumab, with 4-year rates of 52% vs 41%, and median recurrence-free survival of 52.4 months vs 24.1 months (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.60–0.86, P = .0003). Nivolumab improved recurrence-free survival compared with ipilimumab in the IIIB to C and IV disease stage subgroups (HR = 0.71, 95% CI = 0.58–0.88; HR = 0.74, 95% CI = 0.49–1.11, respectively).

Regarding the exploratory endpoint, nivolumab also improved distant metastasis–free survival over ipilimumab in patients with stage III disease, with 4-year rates of 59% vs 53% (HR = 0.79, 95% CI = 0.63–0.99).

With 48 months of follow-up, 211 overall survival events were observed, which was lower than the anticipated 302 events, and in the overall population, there were comparable overall survival rates of 78% with nivolumab and 77% with ipilimumab (HR = 0.87, 95% CI = 0.66–1.14, P = .315).

Improved recurrence-free survival was observed in patients treated with nivolumab with in-transit metastases without nodal involvement, with 4-year rates of 49% vs 41% (HR = 0.73, 95% CI = 0.47–1.12) as well as patients with BRAF-mutant tumors, with rates of 52% vs 44% (HR = 0.79, 95% CI = 0.60–1.05), and BRAF wild-type tumors, with rates of 50% vs 39% (HR = 0.69, 95% CI = 0.53–0.91).

Subsequent systemic therapy was administered to 150 patients (33%) in the nivolumab arm compared with 189 patients (42%) in the ipilimumab arm. A greater proportion of ipilimumab-treated vs nivolumab-treated patients (34% vs 23%) received subsequent systemic immunotherapy.

Of patients who had disease recurrence in the nivolumab arm (n = 212) and ipilimumab arm (n = 253), 69% and 70% of patients received subsequent systemic therapy, respectively, with more patients in the ipilimumab arm (57%) receiving subsequent systemic immunotherapy compared with patients in the nivolumab arm (49%).

More patients in the ipilimumab arm experienced any-grade, late-emergent, treatment-related adverse events (those voluntarily reported > 100 days after the last dose). Late-emergent treatment-related adverse events were reported by 18 patients (4%) in the nivolumab arm vs 25 patients (6%) in the ipilimumab arm. In the respective arms, three patients vs seven patients had grade 3 or 4 late-emergent treatment-related adverse events.

Conclusions

Based upon the 48-month data, which showed nivolumab had sustained improvement of recurrence-free survival and distant metastasis–free survival compared with ipilimumab in patients with stage IIIB to C or IV resected melanoma and a high risk of recurrence, the authors concluded that nivolumab provided superior patient benefit.

With fewer overall survival events than anticipated, the overall survival rates were similar for both agents. More patients in the ipilimumab arm received subsequent therapy, and more ipilimumab-treated patients received subsequent immunotherapy.

No new safety concerns were noted, based on the low rate of voluntarily reported late-emergent treatment-related adverse events.

In addition to this presentation, the analysis of CheckMate 28 was also published by Asicerto et al in The Lancet Oncology.

Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit oncologypro.esmo.org.