FDA Approves Belzutifan-Lenvatinib Combo for Advanced Kidney Cancer

On September 24, the FDA approved the combination of belzutifan (Welireg; Merck) plus lenvatinib (Lenvima; Eisai) to treat adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following a PD-1 or PD-L1 inhibitor.¹

Belzutifan is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, and lenvatinib is an orally available multireceptor tyrosine kinase inhibitor (TKI).² The recommended dosage is 20 mg of lenvatinib in combination with 120 mg of belzutifan once daily until disease progression or unacceptable toxicity.¹

The approval was based on results from the phase 3 LITESPARK-011 trial (NCT04586231), which evaluated belzutifan plus lenvatinib vs cabozantinib (Cabometyx; Exelixis) in patients with advanced ccRCC after treatment with a PD-1 or PD-L1 inhibitor.²

“While there has been much progress in the first-line treatment of advanced kidney cancer, we have limited options to offer patients if the disease progresses after treatment with a PD-1/PD-L1 immunotherapy,” Robert Motzer, MD, LITESPARK-011 principal investigator and genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center, said in a statement. “With this FDA approval of belzutifan plus lenvatinib, we have a new treatment option for patients who progress following treatment with anti-PD-1/PD-L1 therapy—an important development for patients and the physicians who care for them.”

Belzutifan-Lenvatinib Shows PFS, Response Benefits

Results from a prespecified interim analysis showed treatment with belzutifan plus lenvatinib in patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs cabozantinib. Specifically, the combination reduced the risk of disease progression or death by 26% (HR, 0.74; 95% CI, 0.61-0.89; P = .001), with a median PFS of 14.6 months (95% CI, 11.1-16.6) vs 10.6 months (95% CI, 9.2-11.1) with cabozantinib.

Belzutifan plus lenvatinib also demonstrated a statistically significant improvement in objective response rate (ORR), a key secondary end point. The combination had an ORR of 53% (95% CI, 47%-58%) compared with 40% (95% CI, 35%-45%; P = .0002) with cabozantinib.

However, overall survival, the study’s other primary end point, did not meet statistical significance for patients who received belzutifan plus lenvatinib vs cabozantinib in the final analysis. These results will be presented at the European Society for Medical Oncology Congress 2026 in Madrid, Spain, which will take place October 23-27.

Safety Considerations and Expert Perspective

Regarding safety, the belzutifan/lenvatinib combination has warnings and precautions for cardiac dysfunction.¹ Separately, the belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity, along with warnings and precautions for anemia and hypoxia.

As for lenvatinib, the prescribing information includes the following additional warnings and precautions: hypertension, 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, and osteonecrosis of the jaw.

Despite these safety considerations, experts, including M. Catherine Pietanza, MD, vice president of global clinical development at Merck Research Laboratories, described the approval as an important addition to the treatment landscape for patients with advanced kidney cancer.

“By bringing together 2 therapies that each target different pathways, Welireg plus Lenvima is now the first approved regimen of its kind, offering a new treatment option for certain patients with advanced renal cell carcinoma who have progressed after anti-PD-1/PD-L1 therapy,” she said in a news release. “This approval represents real progress for patients and further reinforces the importance of an HIF-2α inhibitor plus TKI combination as a new treatment approach for these patients.”

References

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. News release. FDA. September 24, 2026. Accessed September 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component
2. US FDA approves Welireg (belzutifan) 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. https://www.merck.com/news/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/