LITESPARK-022 is a global phase III study evaluating the addition of belzutifan to pembrolizumab in the adjuvant treatment of patients with clear cell renal cell carcinoma (RCC) following nephrectomy. The trial met its primary endpoint of disease-free survival (DFS), representing the first reported positive adjuvant data for a regimen incorporating a hypoxia-inducible factor-2α (HIF-2α) inhibitor. Detailed efficacy and safety results are scheduled for presentation at the 2026 ASCO Genitourinary Cancers Symposium on February 28, 2026.
Clinical Takeaway
In patients with resected clear cell RCC, pembrolizumab plus belzutifan significantly improved disease-free survival compared with pembrolizumab plus placebo. Overall survival and numerical efficacy results have not yet been publicly reported.
Drug Profile & Mechanism
- Agent:
- pembrolizumab (Keytruda)
- belzutifan (Welireg)
- Class & Mechanism of Action:
- pembrolizumab: Anti–programmed death receptor-1 (PD-1) monoclonal antibody that blocks PD-1 interaction with PD-L1 and PD-L2, enhancing T-cell–mediated antitumor immune responses.
- belzutifan: Selective HIF-2α inhibitor that suppresses hypoxia-driven transcriptional signaling pathways involved in tumor growth and angiogenesis in clear cell RCC.
- Route of Administration & Dosing Schedule:
- pembrolizumab: 400 mg intravenously (IV) every 6 weeks for approximately 1 year
- belzutifan: 120 mg orally once daily for approximately 1 year
Target Population
- Patients with clear cell RCC at increased risk of recurrence following nephrectomy.
LITESPARK-022 Study Design (NCT05239728)
- Study Type: Randomized, multicenter, double-blind phase III clinical trial
- Population: 1,841 patients
- Randomization:
- belzutifan + pembrolizumab
- pembrolizumab + placebo
- Follow-Up Duration:
- Median follow-up: Not publicly disclosed as the trial is ongoing
- Estimated primary completion: October 2026
Endpoints
- Primary Endpoint:
- DFS
- Secondary Endpoints:
- OS
- Safety and Tolerability
Efficacy Outcomes
- Primary Endpoint Results:
- The DFS primary endpoint was met, with pembrolizumab plus belzutifan demonstrating a statistically significant improvement over pembrolizumab plus placebo. Specific hazard ratios, absolute DFS rates, and subgroup analyses have not yet been publicly reported.
- OS: Not yet publicly reported
Safety
- Overall Safety Profile: Consistent with known profiles of each agent.
- Grade ≥3 Events: Not yet publicly reported
- Treatment discontinuation: Not yet publicly reported
- Notable toxicity patterns: Detailed toxicity patterns specific to the combination have not been disclosed.
No new safety signals were identified, and adverse events were generally manageable with standard supportive care and dose modifications.
Regulatory Milestones
- Approval Status: No regulatory approval for the adjuvant combination for clear cell RCC.
- Current Standard of Care: Adjuvant pembrolizumab monotherapy for select patients following nephrectomy.
- Regulatory Pathway: Full trial data are expected to be presented at an upcoming scientific meeting.
Key Clinical Implications
✔ First reported positive DFS data for an adjuvant regimen incorporating HIF-2α inhibition with PD-1 blockade.
✔ Potential paradigm discussion in adjuvant clear cell RCC pending more complete data.
✔ OS and safety details remain key determinants of clinical adoption.
Bottom Line
LITESPARK-022 met its primary endpoint of disease-free survival, demonstrating that the addition of belzutifan may improve DFS compared with pembrolizumab alone in patients with resected clear cell RCC. Full efficacy and safety details are forthcoming.
Sources:
- American Society of Clinical Oncology. (2026). 2026 ASCO Genitourinary Cancers Symposium. https://www.asco.org/gu
- ClinicalTrials.gov. (2026). A study of belzutifan (MK-6482) plus pembrolizumab versus pembrolizumab plus placebo in participants with clear cell renal cell carcinoma following nephrectomy (LITESPARK-022) (NCT05239728). U.S. National Library of Medicine. https://clinicaltrials.gov/study/NCT05239728
- Merck. (2025, October 28). Merck announces KEYTRUDA (pembrolizumab) plus WELIREG (belzutifan) met primary endpoint of disease-free survival (DFS) in certain patients with clear cell renal cell carcinoma (RCC) following nephrectomy. https://www.merck.com/news/merck-announces-keytruda-pembrolizumab-plus-welireg-belzutifan-met-primary-endpoint-of-disease-free-survival-dfs-in-certain-patients-with-clear-cell-renal-cell-carcinoma-rcc-follow/
