Multinational phase 3 trial of adjuvant pembrolizumab plus belzutifan for clear-cell renal-cell carcinoma

Adjuvant pembrolizumab improves disease-free survival and overall survival among patients with resected clear-cell renal-cell carcinoma (ccRCC). The hypoxia-inducible factor 2α inhibitor belzutifan has activity in advanced disease. The multinational phase 3 LITESPARK-022 trial evaluated the combination of adjuvant pembrolizumab plus belzutifan in patients with ccRCC at increased risk for recurrence. In this trial, participants were randomized 1:1 to receive up to nine doses intravenous pembrolizumab 400 mg every 6 weeks and either daily oral belzutifan 120 mg (n=921) or placebo (n=920) for up to 1 year. The primary endpoint was disease-free survival (DFS) as assessed by the investigator. The median time from randomization to data cutoff was 28.4 months (range 15.0-40.1). DFS was significantly higher with pembrolizumab-belzutifan than with pembrolizumab-placebo (HR 0.72; p<0.001); with estimated 24-months DFS rates of 80.7% and 73.7%, respectively. At this interim analysis, with 29% of the final-analysis events observed, overall survival (OS) did not differ significantly between the groups (HR 0.78; p=0.24) with estimated 24-months OS rates 96.2% with pembrolizumab-belzutifan and 95.7% with pembrolizumab-placebo. Grade ≥ 3 adverse events occurred in 52.1% of the participants who received pembrolizumab-belzutifan and in 30.2% of those who received pembrolizumab-placebo. The authors conclude that addition of belzutifan to pembrolizumab improved DFS and increased the risk of grade ≥3 toxic effects in ccRCC participants at increased risk for recurrence (quick take video summary).