Final results from the phase 3 CheckMate 067 trial, presented at the 2024 ESMO Congress and published in The New England Journal of Medicine, demonstrate a significant and lasting improvement in overall survival (OS) and melanoma-specific survival (MSS) with nivolumab (Opdivo), either as monotherapy or in combination with ipilimumab (Yervoy), compared to ipilimumab alone in patients with advanced melanoma. The 10-year data underscore the potential for long-term remission and possible cure in responding patients.
Landmark Survival Data
With a minimum follow-up of 120 months, the median OS was 71.9 months (95% CI, 38.2-114.4) with nivolumab plus ipilimumab versus 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) compared to 19.9 months with ipilimumab (HR, 0.63; 95% CI, 0.52-0.76). The 10-year OS rates were 43%, 37%, and 19% with nivolumab/ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy, respectively (HR, 0.85 between the combination and nivolumab alone; 95% CI, 0.69-1.05).
"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
The median MSS was not reached (NR) with nivolumab plus ipilimumab (95% CI, 71.8-NR) and was 49.4 months (95% CI, 35.1-119.4) with single-agent nivolumab versus 21.9 months (95% CI, 18.1-27.4) with single-agent ipilimumab. This translated to a HR of 0.48 favoring the combination versus single-agent ipilimumab (95% CI, 0.39-0.59) and a HR of 0.59 for single-agent nivolumab versus ipilimumab (95% CI, 0.49-0.73). The 10-year MSS rates were 52%, 44%, and 23%, respectively.
Prognostic Markers
In patients who experienced a 3-year or greater progression-free survival (PFS), the 10-year MSS rates were 96%, 97%, and 88% with the combination, nivolumab alone, and ipilimumab alone, respectively. "In CheckMate 067, PFS plateaued at 3 years, and these analyses were conducted to determine if being alive and progression free at 3 years may be a surrogate for long-term clinical benefit," Larkin explained. "Indeed, these data suggest that PFS at 3 years is a strong surrogate marker for long-term survival with 10-year MSS rates of greater than 96% in the nivolumab-containing arms."
Ten-year MSS rates were also evaluated by depth of response. In the nivolumab/ipilimumab arm, the best tumor burden reduction was 80% or higher in 87% of patients (n = 102) and was between 50% and 80% in 72% of patients (n = 55); these rates occurred in 88% (n = 85) and 75% (n = 32) of those on nivolumab alone, and 80% (n = 24) and 40% (n = 17) in those on the ipilimumab-only arm, respectively.
Safety Profile
There were no new observed safety signals, and no treatment-related deaths have been reported since the 36-month analysis. The incidence of late-emergent, spontaneously reported treatment-related adverse events (TRAEs) was low across all three arms. Any-grade TRAEs occurred in 96%, 87%, and 86% of patients in the combination, single-agent nivolumab, and single-agent ipilimumab arms, respectively; these were grade 3/4 in 63%, 25%, and 30% of patients, respectively.
Any-grade and grade 3/4 TRAEs that led to treatment discontinuation occurred in 45% and 34% of those on the combination arm, respectively, 16% and 9% in those on nivolumab alone, and 17% and 15% of those on ipilimumab alone, respectively. There were two treatment-related deaths on the combination arm compared with one each on the monotherapy arms.
The median MSS in patients with grade 3/4 TRAEs was not reached (95% CI, 71.9-NR) with the combination, not reached in the nivolumab-alone arm (95% CI, NR-NR), and 30.8 months (95% CI, 22.7-62.8) with ipilimumab alone. The 10-year MSS rates in these patients were 54%, 71%, and 29%, respectively. "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," Larkin added.
Trial Design
In the CheckMate 067 trial, 945 patients with previously untreated, unresectable or metastatic melanoma were randomized 1:1:1 to receive 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses then 3 mg/kg of nivolumab every 2 weeks (n = 314); 3 mg/kg of nivolumab every 2 weeks plus ipilimumab-matched placebo (n = 316); or 3 mg/kg of ipilimumab every 3 weeks for 4 doses plus nivolumab-matched placebo (n = 315) until disease progression or unacceptable toxicity. The coprimary end points were progression-free survival (PFS) and OS with either the combination or nivolumab alone vs ipilimumab; secondary outcome measures were objective response rate, descriptive efficacy assessments, and safety. An exploratory end point was MSS. Stratification factors included PD-L1 status (<5% vs ≥5%), BRAF mutation status, and AJCC metastasis stage. The final data cutoff date was April 19, 2024, and the final database lock date was May 16, 2024.
