FDA Approves Belzutifan Plus Lenvatinib Following Immunotherapy in Advanced Clear Cell Renal Cell Carcinoma

Clinical Summary: 

• Regulatory Update: Based on results from the phase 3 LITESPARK-011 trial, the FDA has approved belzutifan in combination with lenvatinib for patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following treatment with a PD-1 or PD-L1 inhibitor.
• Key Outcomes: In this trial, belzutifan plus lenvatinib significantly improved progression-free survival (PFS) compared with cabozantinib, reducing the risk of disease progression or death by 26%. Objective responses were also higher with the combination, while the final overall survival analysis did not demonstrate a statistically significant benefit.
• Clincial Relevance: This approval establishes belzutifan plus lenvatinib as a treatment option following PD-1/PD-L1 therapy in advanced ccRCC, providing a combination of HIF-2α inhibition and multikinase inhibition supported by superior PFS and response compared with cabozantinib.  

The US Food and Drug Administration (FDA) has approved belzutifan (Welireg; Merck) in combination with lenvatinib (Lenvima; Eisai) for adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following PD-1 or PD-L1 inhibitor treatment. 

This approval was supported by findings from the open-label LITESPARK-011 trial, which enrolled 747 patients with locally advanced or metastatic ccRCC who experienced disease progression on or after treatment with a PD-1/PD-L1 inhibitor or within 6 months of completing adjuvant treatment with a PD-1 inhibitor. 

Patients were randomized 1:1 to receive either belzutifan plus lenvatinib or cabozantinib. Primary end points included progression-free survival (PFS), assessed via blinded independent central review according to RECIST v1.1, and overall survival (OS). Key secondary end points included objective response rate (ORR) and safety. 

At analysis, belzutifan plus lenvatinib significantly improved PFS compared with cabozantinib. Median PFS was 14.6 months in the belzutifan plus lenvatinib arm and 10.6 months in the cabozantinib arm, corresponding to a 26% reduction in the risk of diease progression or death (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61 to 0.89; P = .00095).

ORR was also significantly higher with belzutifan plus lenvatinib, at 53% compared with 40% with cabozantinib (P = .0002).

At final OS analysis, median OS was 33.7 months in the belzutifan plus lenvatinib arm and 28.6 months in the cabozantinib arm. However, the difference was not statistically significant (HR, 0.85; 95% CI, 0.70 to 1.03). 

The recommended dosage is 120 mg of belzutifan plus 20 mg of lenvatinib administered once daily until disease progression or unacceptable toxicity. 

Prescribing information includes warnings and precautions associated with lenvatinib 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, thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.

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

Source: 

US Food and Drug Administration. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. Accessed on September 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component