Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma
Published July 1, 2026
N Engl J Med 2026;395:32-43
DOI: 10.1056/NEJMoa2518245
Abstract
Background
Adjuvant pembrolizumab improves disease-free and overall survival among patients with resected clear-cell renal-cell carcinoma. The hypoxia-inducible factor 2α inhibitor belzutifan has activity in advanced disease. Adjuvant pembrolizumab with belzutifan may further improve outcomes in patients with clear-cell renal-cell carcinoma at increased risk for recurrence.
Methods
In this phase 3, double-blind trial, we randomly assigned participants in a 1:1 ratio to receive intravenous pembrolizumab at a dose of 400 mg every 6 weeks (≤9 doses) and either daily oral belzutifan at a dose of 120 mg (pembrolizumab–belzutifan) or placebo (pembrolizumab–placebo) for up to 1 year. The primary end point was disease-free survival as assessed by the investigator; secondary end points included overall survival and safety.
Results
A total of 921 participants were assigned to receive pembrolizumab–belzutifan and 920 were assigned to receive pembrolizumab–placebo. The median time from randomization to the data-cutoff date (August 23, 2025) was 28.4 months (range, 15.0 to 40.1). Disease-free survival was significantly higher with pembrolizumab–belzutifan than with pembrolizumab–placebo (hazard ratio for disease recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87; two-sided P<0.001); the estimated 24-month disease-free survival was 80.7% and 73.7%, respectively. At this interim analysis with 29% of the final-analysis events observed, overall survival did not differ significantly between the groups (hazard ratio for death, 0.78; 95% CI, 0.51 to 1.19; two-sided P=0.24); the estimated 24-month overall survival was 96.2% with pembrolizumab–belzutifan and 95.7% with pembrolizumab–placebo. Adverse events of grade 3 or higher occurred in 52.1% of the participants who received pembrolizumab–belzutifan and in 30.2% of those who received pembrolizumab–placebo.
Conclusions
Treatment with pembrolizumab–belzutifan led to significantly higher disease-free survival, with a greater risk of grade 3 or higher toxic effects, than treatment with pembrolizumab monotherapy after nephrectomy in participants with clear-cell renal-cell carcinoma at increased risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-022 ClinicalTrials.gov number, NCT05239728.)
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Notes
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ). Toni K. Choueiri is supported in part by grants (2P50CA101942-16 and 5P30CA006516-56) from the Dana–Farber/Harvard Cancer Center Program and the Kidney Specialized Programs of Research Excellence, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, Roger and Kathy Marino Fund for Research Acceleration, and Loker Pinard Funds for Kidney Cancer Research at Dana–Farber Cancer Institute. Treatment of the participants at Memorial Sloan Kettering Cancer Center was supported in part by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the participants and their families and caregivers for participating in this trial, all the site personnel, and the employees of Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ), including Rodolfo F. Perini for research supervision, trial oversight, and critical review; Lyna Benaouda, Veronica Burdusel, Lynn Hyde, and Michelle Smith for trial support; Chris Gause, Manasa Ravi, Lei Xu, and Sabrina Shuyan Wan for statistical analysis assistance; M. Catherine Pietanza for trial support and critical review; Ryan Staudt for writing assistance; and Sara Langan and Jennifer Pawlowski for administrative and logistic assistance.
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History
Published online: July 1, 2026
Published in issue: July 2, 2026
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