On September 24, 2026, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg) in combination with lenvatinib (Lenvima) for adults with advanced renal cell carcinoma with a clear cell component following a PD-1 or PD-L1 inhibitor.
What Was Behind the Approval?
The approval was based on LITESPARK-011 (NCT04586231), an open-label, randomized phase 3 trial comparing belzutifan plus lenvatinib with cabozantinib. Trial results appeared in the August 29, 2026 issue of The Lancet in the article “Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial” by Robert J. Motzer and colleagues.
Belzutifan inhibits hypoxia-inducible factor-2 alpha (HIF-2α), while lenvatinib is a multitargeted tyrosine kinase inhibitor. LITESPARK-011 evaluated the two drugs together in patients whose disease had progressed following PD-1 or PD-L1 inhibitor treatment. Cabozantinib, another tyrosine kinase inhibitor, served as the active comparator.
Earlier Findings Announced by Merck and Eisai
On October 28, 2025, Merck and Eisai announced in a news release that LITESPARK-011 had met its progression-free survival (PFS) endpoint at a prespecified interim analysis. The companies also reported a statistically significant improvement in objective response rate (ORR) with belzutifan plus lenvatinib compared with cabozantinib. Overall survival (OS) had not reached statistical significance at that analysis. The announcement described the findings before detailed results were reported in the journal publication and before the FDA’s final OS analysis.
How Was LITESPARK-011 Conducted?
LITESPARK-011 randomized 747 patients with advanced clear cell renal cell carcinoma: 371 to belzutifan plus lenvatinib and 376 to cabozantinib. The study was conducted at 184 medical centers in 25 countries.
Eligible patients had locally advanced or metastatic disease that progressed on or after a PD-1 or PD-L1 inhibitor. Patients whose disease progressed within six months of completing adjuvant treatment with a PD-1 inhibitor were also eligible. The published trial included patients with and without previous exposure to a VEGF receptor tyrosine kinase inhibitor.
Patients in the combination group received belzutifan 120 mg plus lenvatinib 20 mg orally once daily. Those in the comparator group received cabozantinib 60 mg orally once daily. Study treatment continued until disease progression or unacceptable adverse events, among other protocol-defined reasons for stopping treatment.
The trial had two primary endpoints: PFS and OS. PFS was assessed by blinded independent central review using RECIST v1.1. ORR was an additional efficacy outcome. Although the trial was open-label, the reviewers assessing scans for the PFS endpoint were blinded to treatment assignment.
What Did the FDA Report?
In the analysis presented in the FDA approval notice, median PFS was 14.6 months (95% CI, 11.1–16.6) with belzutifan plus lenvatinib and 10.6 months (95% CI, 9.2–11.1) with cabozantinib. The hazard ratio was 0.74 (95% CI, 0.61–0.89; one-sided P = .00095). This was a statistically significant improvement in PFS with the combination.
ORR was 53% (95% CI, 47%–58%) in the belzutifan–lenvatinib group and 40% (95% CI, 35%–45%) in the cabozantinib group (one-sided P = .0002). Thus, the combination improved both the trial’s PFS outcome and its additional response outcome compared with cabozantinib.
At the final OS analysis, median OS was 33.7 months (95% CI, 29.0–46.9) with belzutifan plus lenvatinib and 28.6 months (95% CI, 24.1–31.4) with cabozantinib. The hazard ratio was 0.85 (95% CI, 0.70–1.03). The OS difference was not statistically significant. The numerical difference between the medians should therefore not be presented as a demonstrated survival benefit.
Additional Findings From the Published Trial
The Lancet article reported the trial’s second interim analysis, with a data cutoff of April 9, 2025 and a median follow-up of 29.0 months. This analysis included the trial’s final PFS assessment and an interim OS assessment. Median PFS was 14.8 months with belzutifan plus lenvatinib versus 10.7 months with cabozantinib (hazard ratio, 0.70; 95% CI, 0.59–0.84; one-sided P < .0001).
The publication also reported how many patients remained alive without progression at specific time points. At 12 months, the estimated proportions were 55% with the combination and 41% with cabozantinib. At 24 months, they were 36% and 19%, respectively. These are findings from the published second interim analysis, separate from the PFS estimates listed in the FDA notice.
Among patients with a partial or complete response at that interim analysis, median duration of response was 23.0 months (95% CI, 18.3–29.3) with belzutifan plus lenvatinib and 12.3 months (95% CI, 9.7–16.6) with cabozantinib. Complete responses were reported in 20 patients (5%) and four patients (1%), respectively.
The FDA notice gives slightly different PFS medians from those in The Lancet and also provides the final OS analysis. The notice does not explain the difference between its PFS estimates and the published estimates. The results from the two sources should therefore remain labeled by source and analysis.
Safety and Patient-Reported Outcomes
Safety results in the Lancet article came from the second interim analysis. Grade 3 or higher treatment-emergent adverse events occurred in 311 of 370 patients (84%) who received belzutifan plus lenvatinib and 307 of 371 patients (83%)who received cabozantinib. Serious treatment-emergent adverse events were reported in 52% and 44% of patients, respectively.
The most common adverse event of any grade was anemia in the combination group, reported in 256 patients (69%), and diarrhea in the cabozantinib group, reported in 260 patients (70%). Hypertension was the most common grade 3 or higher adverse event in both groups, occurring in 114 patients (31%) who received the combination and 107 patients (29%) who received cabozantinib. Treatment-related adverse events led to two deaths in the combination group and one in the cabozantinib group.
The trial also assessed patient-reported outcomes. In the published analysis, time to worsening of disease-related symptoms and health-related quality of life was similar between treatment groups. These findings provide context for the efficacy and safety results but do not alter the final OS finding.
For prescribing, the FDA highlights belzutifan’s boxed warning for embryo-fetal toxicity and its warnings and precautions for anemia and hypoxia. Warnings and precautions for belzutifan used with lenvatinib also include cardiac dysfunction. Lenvatinib has additional warnings and precautions, including hypertension, arterial thromboembolic events, hepatotoxicity, renal impairment, proteinuria, diarrhea, gastrointestinal perforation, QT interval prolongation, and hemorrhagic events.
Recommended Dosage and Interpretation
The FDA-recommended dosage is lenvatinib 20 mg with belzutifan 120 mg once daily until disease progression or unacceptable toxicity. LITESPARK-011’s open-label design is one limitation when interpreting its findings, although PFS was assessed by blinded independent central review.
The trial authors also noted that subgroup analyses were exploratory and that the study design could not determine the individual contribution of each drug to the combination’s effect. These limitations sit alongside the central result: belzutifan plus lenvatinib improved PFS compared with cabozantinib, while a statistically significant OS benefit was not demonstrated.
Takeaway
Belzutifan plus lenvatinib is now FDA-approved for adults with advanced renal cell carcinoma with a clear cell component following a PD-1 or PD-L1 inhibitor. In LITESPARK-011, the combination significantly improved PFS and produced a higher ORR than cabozantinib. The final OS analysis did not show a statistically significant difference.
Full details of the approval are available on official FDA website.
Read more about Metastatic Renal Cell Carcinoma in 2026 on OncoDaily.
