FDA has approved the dual oral regimen of Welireg (belzutifan), Merck's first-in-class oral hypoxia-inducible factor-2 alpha inhibitor, plus Lenvima (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for adult patients with advanced renal cell carcinoma with a clear cell component following a programmed death receptor-1 or programmed death-ligand 1 inhibitor.

By combining two therapies that target different pathways, Welireg plus Lenvima becomes the first approved regimen of its kind for patients who have progressed after anti-PD-1/PD-L1 therapy, establishing a HIF-2α inhibitor plus tyrosine kinase inhibitor combination as a new treatment approach in a setting where options have been limited.¹

"This approval represents real progress for patients and further reinforces the importance of a HIF-2α inhibitor plus TKI combination as a new treatment approach for these patients," said Dr. M. Catherine Pietanza, vice president, global clinical development, at Merck Research Laboratories.

What is the approval based on?

The approval is based on the Phase III Litespark-011 trial, a randomized, open-label study of 747 patients comparing Welireg plus Lenvima against cabozantinib in advanced clear cell renal cell carcinoma that had progressed on or after a PD-1 or PD-L1 inhibitor.² Patients receivied Welireg 120 mg plus Lenvima 20 mg orally once daily, or cabozantinib 60 mg once daily, with dual primary endpoints of progression-free survival and overall survival.²

A pre-specified interim analysis showed Welireg plus Lenvima reduced the risk of disease progression or death by 26% compared with cabozantinib (hazard ratio 0.74; 95% CI, 0.61-0.89; p=0.001), with median progression-free survival of 14.6 months versus 10.6 months.² The combination also significantly improved objective response rate, a key secondary endpoint, at 53% versus 40% (p=0.0002).² At the final analysis, overall survival, the trial's other primary endpoint, did not reach statistical significance. Results will be presented at the upcoming European Society for Medical Oncology Congress 2026 in Madrid.

"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," said Dr. Robert Motzer, principal investigator and genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center. "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."

How does this fit into the broader RCC landscape?

Lenvima is already approved in the U.S. in combination with Keytruda (pembrolizumab) or Keytruda Qlex for first-line advanced renal cell carcinoma, and Welireg is also approved as a monotherapy following a PD-1 or PD-L1 inhibitor and a VEGF-TKI, and in combination with Keytruda or Keytruda Qlex for adjuvant treatment of high-risk disease after nephrectomy.

The new approval extends that combination franchise into disease progression after anti-PD-1/PD-L1 therapy, positioning Welireg plus Lenvima to compete directly against cabozantinib, the standard it was tested against.

Sources

1. 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) Merck 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/ 
2. A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011) National Library of Medicine May 5, 2026, https://clinicaltrials.gov/study/NCT04586231