Long-term data from the phase 3 CheckMate 067 trial reveal that the combination of nivolumab and ipilimumab provides a significant and durable survival benefit for patients with advanced melanoma. The 10-year follow-up, involving 945 patients across 137 sites in 21 countries, demonstrates a substantial improvement in overall survival compared to ipilimumab alone, marking a significant shift in the treatment landscape for this aggressive cancer. The study, presented at the 2024 ESMO Congress and published in The New England Journal of Medicine, offers new hope for long-term disease control and potential cure.
Landmark Trial Demonstrates Unprecedented Survival
The CheckMate 067 trial compared the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) to nivolumab alone and ipilimumab alone in patients with previously untreated, unresectable or metastatic melanoma. The results showed a median overall survival (OS) of 71.9 months (95% CI, 38.2-114.4) with nivolumab plus ipilimumab, compared to 19.9 months (95% CI, 16.8-24.6) with ipilimumab alone (HR, 0.53; 95% CI, 0.44-0.65). Nivolumab monotherapy resulted in a median OS of 36.9 months (95% CI, 28.2-58.7), with a HR of 0.63 (95% CI, 0.52-0.76) compared to ipilimumab.
"The 10-year CheckMate 067 results for nivolumab plus ipilimumab represent the longest median OS in a phase 3 study of an anti–PD-1 agent for any tumor type," said lead study author James Larkin, MD, professor and consultant medical oncologist at The Royal Marsden Hospital in the United Kingdom. "These results demonstrate the sustained benefit and impact of dual checkpoint inhibitor therapy on the long-term prognosis of patients with advanced melanoma, highlighting the potential for cure in patients who respond to this type of treatment."
Melanoma-Specific Survival and Long-Term Outcomes
In addition to overall survival, the study assessed melanoma-specific survival (MSS), revealing a median MSS that was not reached (NR) with nivolumab plus ipilimumab (95% CI, 71.8-NR) and 49.4 months (95% CI, 35.1-119.4) with single-agent nivolumab, compared to 21.9 months (95% CI, 18.1-27.4) with single-agent ipilimumab. The 10-year MSS rates were 52%, 44%, and 23%, respectively. Notably, in patients who were alive and progression-free at 3 years, the 10-year MSS rates were 96% with the combination, 97% with nivolumab alone, and 88% with ipilimumab alone, suggesting that PFS at 3 years is a strong surrogate marker for long-term survival.
Safety Profile and Tolerability
The 10-year analysis found no new safety signals for the treatment. While any-grade treatment-related adverse events (TRAEs) occurred in 96% of patients in the combination arm, 87% in the nivolumab arm, and 86% in the ipilimumab arm, the incidence of late-emergent TRAEs was low across all arms. Grade 3/4 TRAEs leading to treatment discontinuation occurred in 45% of those on the combination arm, 16% on nivolumab alone, and 17% on ipilimumab alone. Importantly, TRAEs did not negatively affect survival, as 10-year MSS rates in patients with a grade 3/4 TRAE were higher than in the intent-to-treat population within each treatment arm.
Implications for Clinical Practice
The long-term data from CheckMate 067 provide valuable insights for clinical practice, potentially influencing post-treatment follow-up strategies. Patients who achieve long-term survival may require less frequent surveillance, reducing the burden of ongoing testing while maintaining effective care. Moreover, the study reinforces the potential of immune checkpoint inhibitors to transform metastatic melanoma into a manageable, long-term condition. As Dr. F. Stephen Hodi, Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber, stated, "After a decade of follow-up, we can now confidently tell our patients that there are treatments available with the potential to transform metastatic melanoma into a manageable, long-term condition, instilling confidence about the future."
