LITESPARK-005

LITESPARK-005, trial NCT04195750 sponsored by Merck and reported in 2023, showed that the HIF-2-alpha inhibitor belzutifan beats the old standard everolimus in advanced clear-cell renal cell carcinoma after immunotherapy and a VEGF kinase inhibitor have failed, with durable responses in a subset. It randomised 746 patients, met its primary progression-free survival endpoint with a much higher response rate, did not significantly improve overall survival, and led to FDA approval in December 2023, with anaemia and low oxygen as on-mechanism toxicities. OnCo links it to renal cell carcinoma, HIF-2-alpha as a target, belzutifan, everolimus, Laurence Albiges and Toni K. Choueiri, and belzutifan's activity was also shown in VHL disease in LITESPARK-004 while the first-line combination LITESPARK-012 failed in 2026. Whether the responders can be identified in advance is the open question.