Belzutifan plus lenvatinib cleared for advanced clear cell RCC

On September 24, 2026, the Food and Drug Administration approved belzutifan (Welireg, Merck & Co., Inc.) in combination with lenvatinib (Lenvima, Eisai Inc.) 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.

Full prescribing information for Welireg and Lenvima will be posted on Drugs@FDA.

Efficacy and Safety

Efficacy was evaluated in LITESPARK-011 (NCT04586231), an open-label, randomized, active-controlled trial in 747 patients with advanced ccRCC. Eligible patients had locally advanced or metastatic ccRCC which progressed on or after a PD-1 or PD-L1 inhibitor, or within six months of completing adjuvant therapy with a PD-1 inhibitor. Patients were randomized (1:1) to receive either belzutifan and lenvatinib or cabozantinib.

The major efficacy outcome measures were progression-free survival (PFS) measured by blinded independent central review using RECIST v1.1 and overall survival (OS). Objective response rate (ORR) was an additional efficacy outcome measure. There was a statistically significant improvement in PFS for the belzutifan and lenvatinib arm compared to the cabozantinib arm. Median PFS was 14.6 months (95% CI: 11.1, 16.6) in the belzutifan and lenvatinib arm and 10.6 months (95% CI: 9.2, 11.1) in the cabozantinib arm (Hazard Ratio 0.74 [95% CI: 0.61, 0.89]; one-sided p-value 0.00095). The final analysis of OS was not statistically significant. Median OS was 33.7 months (95% CI: 29.0, 46.9) and 28.6 months (95% CI: 24.1, 31.4) in the respective arms (Hazard Ratio 0.85 [95% CI: 0.70, 1.03]). ORR was 53% (95% CI: 47, 58) and 40% (95% CI: 35, 45) in the respective arms (one-sided p-value 0.0002).

The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity, as well as warnings and precautions for anemia and hypoxia. For the belzutifan and lenvatinib combination, warnings and precautions also include cardiac dysfunction.

The lenvatinib prescribing information includes warnings and precautions for hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.

Recommended Dosage

The recommended dosage is 20 mg of lenvatinib in combination with 120 mg of belzutifan once daily until disease progression or unacceptable toxicity.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.