RCT: Nivolumab Plus Ipilimumab Shows Sustained 10-Year Survival Benefit in Advanced Melanoma
18 Sep, 2024 | 15:06h | UTCBackground: Advanced melanoma historically had a poor prognosis, with median survival under 12 months before 2011. The advent of immune checkpoint inhibitors like nivolumab (anti–PD-1) and ipilimumab (anti–CTLA-4) has significantly improved outcomes. Previous results from the CheckMate 067 trial showed longer overall survival with nivolumab plus ipilimumab or nivolumab alone compared to ipilimumab alone. As patients now live beyond 7.5 years, longer-term data are needed to address new clinical questions about survival and disease progression.
Objective: To assess the final 10-year outcomes of overall survival, melanoma-specific survival, and response durability in patients with advanced melanoma treated with nivolumab plus ipilimumab, nivolumab monotherapy, or ipilimumab monotherapy.
Methods: In the phase 3 CheckMate 067 trial, 945 patients with untreated, unresectable stage III or IV melanoma were randomized 1:1:1 to receive:
- Nivolumab plus ipilimumab: Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for four doses, then nivolumab (3 mg/kg) every 2 weeks.
- Nivolumab monotherapy: Nivolumab (3 mg/kg) every 2 weeks plus placebo.
- Ipilimumab monotherapy: Ipilimumab (3 mg/kg) every 3 weeks for four doses plus placebo.
Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Randomization was stratified by BRAF mutation status, metastasis stage, and PD-L1 expression. Primary endpoints were overall survival and progression-free survival; secondary endpoints included objective response rates and subgroup analyses.
Results: After 10 years, median overall survival was:
- 71.9 months with nivolumab plus ipilimumab,
- 36.9 months with nivolumab,
- 19.9 months with ipilimumab.
Hazard ratios for death were 0.53 (95% CI, 0.44–0.65; P<0.001) for nivolumab plus ipilimumab vs. ipilimumab, and 0.63 (95% CI, 0.52–0.76; P<0.001) for nivolumab vs. ipilimumab. Ten-year overall survival rates were 43% with combination therapy, 37% with nivolumab, and 19% with ipilimumab. Median melanoma-specific survival was not reached (>120 months) with combination therapy (37% alive at study end), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with combination therapy, 97% with nivolumab, and 88% with ipilimumab. No new safety signals were observed over the extended follow-up.
Conclusions: Nivolumab plus ipilimumab demonstrated a sustained 10-year survival benefit over ipilimumab monotherapy in advanced melanoma. Nivolumab monotherapy also improved survival compared to ipilimumab, though the combination provided the greatest benefit.
Implications for Practice: These 10-year results support nivolumab plus ipilimumab as a preferred first-line treatment for advanced melanoma, offering potential for long-term survival and possible cure. Clinicians should balance improved efficacy against higher adverse event rates with combination therapy and monitor patients accordingly.
Study Strengths and Limitations: Strengths include the large, randomized, multicenter design and extended follow-up, providing robust survival data. Limitations include the trial not being powered for formal comparison between combination and monotherapy, and potential confounding from subsequent therapies on long-term outcomes.
Future Research: Further studies should aim to identify biomarkers predicting long-term response, optimize patient selection for combination therapy, and develop treatments for patients unresponsive to current immune checkpoint inhibitors.