Adjuvant pembrolizumab plus belzutifan versus placebo in clear cell renal cell carcinoma: a reconstructed survival data analysis of the KEYNOTE-564 and the LITESPARK-022 trials.

BACKGROUND: Adjuvant pembrolizumab improves disease-free survival (DFS) and overall survival (OS) versus placebo in high-risk clear cell renal cell carcinoma after nephrectomy. Recently, pembrolizumab plus belzutifan showed superior DFS over pembrolizumab alone. We assessed the efficacy of adjuvant pembrolizumab plus belzutifan versus placebo using reconstructed data from two pivotal phase III trials. METHODS: Individual time-to-event data were reconstructed from digitised KEYNOTE-564 and LITESPARK-022 Kaplan-Meier curves using a validated algorithm based on numbers at risk. Datasets were pooled to enable indirect comparisons across strategies. The primary endpoint was DFS and OS was secondary. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. FINDINGS: The pooled dataset included 2835 patients. Baseline characteristics were balanced, except for race and programmed death-ligand 1 (PD-L1), although PD-L1 assessment was limited by incomplete reporting. Pembrolizumab plus belzutifan significantly improved DFS versus placebo (HR 0.55, 95% CI 0.45-0.69, P < 0.001). Despite immature OS data, the combination showed an OS benefit over placebo (HR 0.56, 95% CI 0.35-0.89, P = 0.014). CONCLUSIONS: Adjuvant pembrolizumab plus belzutifan showed a substantial DFS benefit compared with placebo. In a context where factors beyond efficacy demand robust evidence of clinical benefit, these findings reinforce the value of combined immune and hypoxia-inducible factor 2α inhibition.