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.
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.
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.)
LITESPARK-022 is the first phase 3 trial to build on top of adjuvant pembrolizumab – rather than placebo or surveillance – by adding the HIF-2α inhibitor belzutifan in patients with resected clear cell renal cell carcinoma (ccRCC) at intermediate-to-high or high risk of recurrence, or with M1 no-evidence-of-disease status (1). Across 1841 randomised participants, the combination significantly improved disease-free survival (DFS) over pembrolizumab monotherapy (24-month DFS 80.7% vs. 73.7%; HR 0.72, 95% CI 0.59–0.87; P<0.001), at the cost of an increase in grade ≥3 toxicity (52.1% vs. 30.2%), driven predominantly by anaemia and hypoxia. Overall survival (OS) was numerically but not statistically better (HR 0.78, 95% CI 0.51–1.19) at this early interim analysis, with only 29% of the planned OS events observed.
When positioning these new data within the adjuvant RCC landscape, LITESPARK-022 follows a decade of largely negative VEGFR-TKI adjuvant trials and strikingly mixed results of adjuvant immunotherapy trials. KEYNOTE-564 remains the only adjuvant regimen with a confirmed OS benefit (HR 0.62, 95% CI 0.44–0.87) and is the established standard of care on which LITESPARK-0225 is the first to build (2). Baseline characteristics in LITESPARK-022 were broadly similar to those of KEYNOTE-564, though with a slightly higher proportion of M1-NED disease and grade 4 tumours, which might further complicate any cross-trial comparison of absolute DFS rates (78.2% at 24 months in the KEYNOTE-564 pembrolizumab arm vs. 73.7% in the pembrolizumab monotherapy arm of LITESPARK-022). The relative treatment effect, however, is consistent (HR 0.68–0.72 in both trials), and reassuringly the DFS curves in LITESPARK-022 remain separated well beyond the 1-year on-treatment period, arguing against a purely treatment-duration artifact.
The statistical significance of the DFS benefit is not in question. What is far less settled is whether this translates into a survival advantage that justifies the additional toxicity in a population that, by definition, has no evidence of disease at the time of treatment. The OS analysis is immature (87 of a planned 300 events), and the early hazard ratio, while directionally favourable, is wide and non-significant. However, a supportive signal comes from distant metastasis-free survival (HR 0.71, 95% CI 0.59–0.87), which may be an earlier-maturing surrogate and could indicate a future OS benefit. Notably, the OS benefit in KEYNOTE-564 itself only became clear well after the first interim analysis, so longer follow-up in LITESPARK-022 is essential before drawing firm conclusions. Thus, the DFS benefit is real, but the OS question is not yet answered.
Grade ≥3 adverse events nearly doubled with the addition of belzutifan (52.1% vs. 30.2%), with anaemia (grade ≥3 in 12.1% vs. 0.4%) and hypoxia (7.0% vs. 0.1%) as the principal drivers, alongside more frequent treatment discontinuation and dose interruption. These effects mirror what is already known from belzutifan monotherapy and are generally manageable and reversible, but they are not trivial in patients who may already be cured by surgery alone. Real-world uptake data for pembrolizumab monotherapy after KEYNOTE-564 coming from the US show that around two thirds of eligible patients receive adjuvant pembrolizumab, reflecting that a substantial proportion of patients or physicians do not receive adjuvant treatment (3). Health-related quality of life data from LITESPARK-022 will be essential to further weigh risks and benefits of such treatment, considering the potential added toxicity burden in this shared decision-making process.
Overall, LITESPARK-022 clearly pushes the field of adjuvant RCC treatment further and clearly reduces recurrences. It does not, at this stage, convincingly limit toxicity, and whether it improves survival remains unknown. Therefore, it seems a reasonable option to discuss with well-informed patients at higher risk, pending mature OS and quality-of-life data. However, these data again reinforce the need to move away from a one-size-fits-all adjuvant strategy based on historical risk of recurrence, that exposes many surgically cured patients to unnecessary toxicity. Biomarkers of minimal residual disease – such as elevated serum KIM-1, shown to be both prognostic and predictive in the IMmotion010 biomarker analysis – offer a promising path toward selecting the patients most likely to benefit from treatment intensification, and should be prioritised in future adjuvant RCC trial design (4).
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