FDA Approves Belzutifan-Lenvatinib for Advanced ccRCC

The FDA has approved belzutifan (Welireg, Merck) in combination with lenvatinib (Lenvima, Eisai) for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Belzutifan is an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, and lenvatinib is an oral multiple receptor tyrosine kinase inhibitor, according to Merck and Eisai. The companies described the regimen as the first approved combination of a HIF-2α inhibitor and a multitargeted VEGFR-TKI for these patients. The recommended dosage is belzutifan 120mg plus lenvatinib 20mg once daily until disease progression or unacceptable toxicity.

The approval was based on the open-label, randomized, active-controlled phase 3 LITESPARK-011 trial, which enrolled 747 patients with locally advanced or metastatic ccRCC that progressed on or after a PD-1 or PD-L1 inhibitor or within 6 months of completing adjuvant PD-1 inhibitor therapy. Patients were randomly assigned 1:1 to belzutifan plus lenvatinib or cabozantinib. Median progression-free survival (PFS) by blinded independent central review was 14.6 months (95% CI, 11.1-16.6) vs 10.6 months (95% CI, 9.2-11.1), respectively (hazard ratio [HR], 0.74; 95% CI, 0.61-0.89; one-sided P=0.00095). Objective response rate was 53% vs 40% (one-sided P=0.0002). The final overall survival analysis, a co-primary measure, was not statistically significant (median, 33.7 vs 28.6 months; HR, 0.85; 95% CI, 0.70-1.03).

Belzutifan labeling includes a boxed warning for embryo-fetal toxicity and warnings and precautions for anemia and hypoxia, with cardiac dysfunction added for the combination, the FDA said. Lenvatinib labeling includes warnings and precautions for hypertension, cardiac dysfunction, hepatotoxicity, renal failure or impairment, proteinuria, hemorrhagic events, and other risks. According to the companies, serious adverse reactions occurred in 54% of patients receiving the combination and fatal adverse reactions in 5%.

Merck and Eisai said the results will be presented at the European Society for Medical Oncology Congress 2026. The FDA said full prescribing information for both drugs will be posted on Drugs@FDA.

Sources: US Food and Drug Administration. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. US Food and Drug Administration; September 24, 2026. Accessed September 25, 2026.

Merck. U.S. FDA approves WELIREG (belzutifan) plus LENVIMA (lenvatinib) for certain previously treated adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC). News release. Merck; September 25, 2026. Accessed September 25, 2026.