Phase 3 belzutifan HIF-2α inhibitor + zanzalintinib multi-kinase VEGFR/c-MET inhibitor in advanced RCC.

Merck Sharp & Dohme (MSD) is running LITESPARK-034 (MK-6482-034), a Phase 3 randomized, double-blind study testing belzutifan plus zanzalintinib versus belzutifan plus placebo in advanced/unresectable renal cell carcinoma that has progressed after both PD-1/PD-L1 therapy and a VEGF TKI (given sequentially or together). Belzutifan (Merck; WELIREG) is a small-molecule HIF-2α inhibitor that targets the hypoxia signaling pathway central to clear cell RCC biology, while zanzalintinib (Exelixis collaborator asset) is an oral small-molecule inhibitor that targets VEGFR and c-MET (HGFR), aiming to deepen and prolong disease control versus belzutifan alone. Participants receive daily oral therapy for up to ~24 months, with dual primary focus on overall survival and progression-free survival. The commercial/scientific angle is positioning a chemotherapy-free, all-oral targeted doublet in the common post–IO + post–VEGF-TKI setting, where today’s care is typically more VEGF-pathway TKIs (e.g., cabozantinib/lenvatinib) and/or other later-line agents, with limited durable benefit for many patients.