Merck and Eisai announced US FDA approval of Welireg (belzutifan) plus Lenvima (lenvatinib) for adults with advanced renal cell carcinoma with a clear cell component following treatment with a PD-1 or PD-L1 inhibitor. The dual oral regimen is the first approved combination of a HIF-2α inhibitor and a multi-targeted VEGFR tyrosine kinase inhibitor in this setting.
The approval was based on the Phase III LITESPARK-011 study, which compared belzutifan plus lenvatinib with cabozantinib in previously treated advanced clear cell RCC. At a prespecified interim analysis, the combination reduced the risk of disease progression or death by 26% versus cabozantinib, with median progression-free survival of 14.6 months compared with 10.6 months (HR 0.74; 95% CI 0.61–0.89; p=0.001). Objective response rates were 53% and 40%, respectively. Overall survival, the study’s other primary endpoint, did not reach statistical significance at the final analysis.
Belzutifan inhibits HIF-2α, a transcription factor that becomes constitutively active in most clear cell RCC as a result of VHL pathway disruption, while lenvatinib inhibits VEGFR and other receptor tyrosine kinases involved in tumor angiogenesis. The combination therefore targets the disease through complementary HIF-2α and angiogenic pathways.
The approval further expands the role of belzutifan in renal cell carcinoma. The drug was first approved in December 2023 as monotherapy for advanced RCC following both PD-(L)1 and VEGF-targeted therapy, and in June 2026 gained an additional approval in combination with pembrolizumab for adjuvant treatment of certain patients with resected clear cell RCC, as previously reported.