FDA Approves Belzutifan Plus Lenvatinib for Advanced ccRCC

The FDA has approved belzutifan (Welireg) plus lenvatinib (Lenvima) for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) after a PD-1 or PD-L1 inhibitor.¹

This regulatory decision was backed by data from the open-label, randomized, active-controlled, LITESPARK-011 trial (NCT04586231). The belzutifan combination significantly improved progression-free survival vs cabozantinib (Cabometyx), at a median of 14.6 months (95% CI, 11.1-16.6) and 10.6 months (95% CI, 9.2-11.1), respectively (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095).

Although the combination led to a numerical improvement in overall survival (OS) vs single-agent cabozantinib, the difference between the arms was not determined to be staistically significant. The median OS in the respective arms was 33.7 months (95% CI, 29.0-46.9) and 28.6 months (95% CI, 24.1-31.4), translating to a hazard ratio of 0.85 (95% CI, 0.70-1.03).

Moreover, belzutifan plus lenvatinib induced an objective response rate (ORR) of 53% (95% CI, 47%-58%), which was slightly higher than the 40% (95% CI, 35%-45%) achieved with cabozantinib (1-sided P = .0002).

What was the design of LITESPARK-011?

This trial enrolled 747 patients with locally advanced or metastatic ccRCC who had progressed during or after treatment with a PD-1 or PD-L1 inhibitor, or within 6 months of completing adjuvant therapy with a PD-1 inhibitor. Patients were randomly assigned 1:1 to receive either belzutifan plus lenvatinib, or cabozantinib.

The primary objective of the study was PFS by blinded independent central review and RECIST v1.1 criteria, as well as OS. An additional efficacy outcome measure of interest was ORR.

The recommended dosage for the regimen is lenvatinib at 20 mg plus belzutifan at 120 mg given once daily until progressive disease or intolerable toxicity.

Reference

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