Adjuvant pembrolizumab has improved outcomes for patients with resected clear-cell renal-cell carcinoma at increased risk for recurrence. Belzutifan, a hypoxia-inducible factor 2α inhibitor, has shown activity in advanced clear-cell RCC, supporting evaluation of the combination in the adjuvant setting.
On July 1, 2026, The New England Journal of Medicine published results from LITESPARK-022, a phase 3 trial evaluating adjuvant pembrolizumab plus belzutifan versus pembrolizumab plus placebo after surgery in patients with clear-cell renal-cell carcinoma.
The article, titled “Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma,” was published in NEJM, Volume 395, Issue 1.
Authors: Toni K. Choueiri, Robert J. Motzer, Jose A. Karam, Wesley Yip, Cristina Suárez, Dingwei Ye, Zhisong He, Christian Caglevic, Tom Ferguson, Yen-Hwa Chang, Carlos Rojas, Roberto Iacovelli, Yüksel Ürün, Elena Verzoni, Juan Carlos Vázquez Limón, Camillo Porta, Robert G. Uzzo, Jae Lyun Lee, Balaji Venugopal, Rana R. McKay, Hans Hammers, Hideaki Miyake, Jad Chahoud, Hong Liu, Joseph E. Burgents, Manish Sharma, and Thomas B. Powles, for the LITESPARK-022 Investigators.
About LITESPARK-022
LITESPARK-022 was a phase 3, double-blind, multinational trial. Eligible participants were adults with histologically confirmed, surgically resected clear-cell renal-cell carcinoma at intermediate-to-high risk or high risk for recurrence, or with M1 disease with no evidence of disease after complete resection.
Participants were randomly assigned 1:1 to receive pembrolizumab 400 mg intravenously every 6 weeks for up to 9 doses, with either oral belzutifan 120 mg daily or placebo for up to 1 year. The primary endpoint was investigator-assessed disease-free survival. Secondary endpoints included overall survival and safety.
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Key Results
A total of 1,841 participants were randomized: 921 to pembrolizumab plus belzutifan and 920 to pembrolizumab plus placebo. The median time from randomization to data cutoff was 28.4 months.
Disease-free survival was significantly higher with pembrolizumab plus belzutifan compared with pembrolizumab plus placebo.
At data cutoff, recurrence or death occurred in 186 participants in the pembrolizumab–belzutifan group and 246 participants in the pembrolizumab–placebo group.
The estimated 24-month disease-free survival rate was 80.7% with pembrolizumab plus belzutifan and 73.7% with pembrolizumab plus placebo. The hazard ratio for recurrence or death was 0.72, with a 95% confidence interval of 0.59 to 0.87.
At 30 months, estimated disease-free survival was 75.8% and 68.6%, respectively. A central-review sensitivity analysis also favored the combination, with a hazard ratio for recurrence or death of 0.76.
Overall survival data were immature at this interim analysis. Death occurred in 38 participants in the pembrolizumab–belzutifan group and 49 participants in the pembrolizumab–placebo group. The estimated 24-month overall survival rate was 96.2% and 95.7%, respectively. The hazard ratio for death was 0.78, with a 95% confidence interval of 0.51 to 1.19.
Safety
Adverse events of any cause occurred in 98.9% of participants receiving pembrolizumab plus belzutifan and 94.5% of those receiving pembrolizumab plus placebo. Grade 3 or higher adverse events were more frequent with the combination: 52.1% versus 30.2%.
Serious adverse events occurred in 29.5% and 19.9% of participants, respectively. Adverse events led to discontinuation of pembrolizumab, belzutifan or placebo, or both in 34.3% of participants in the pembrolizumab–belzutifan group and 19.5% in the pembrolizumab–placebo group.
Anemia was more common with pembrolizumab plus belzutifan, occurring in 84.0% of participants, including grade 3 or higher anemia in 12.1%. In the pembrolizumab–placebo group, anemia occurred in 11.4%, with grade 3 or higher anemia in 0.4%. Hypoxia occurred in 7.0% of participants receiving pembrolizumab plus belzutifan and 0.1% receiving pembrolizumab plus placebo. Treatment-related adverse events leading to death occurred in 0.3% of participants in each group.
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Conclusion
In LITESPARK-022, adjuvant pembrolizumab plus belzutifan improved disease-free survival compared with pembrolizumab monotherapy in patients with clear-cell renal-cell carcinoma at increased risk for recurrence after nephrectomy or nephrectomy with resection of metastatic lesions.
The combination was associated with more grade 3 or higher adverse events, particularly anemia. Overall survival data were immature at the time of this interim analysis.
The full article is available in The New England Journal of Medicine.