The first-in-class HIF-2α selective inhibitor, belzutifan, which blocks the heterodimerization of HIF-2α with HIF-1β, shows promising single-agent activity in heavily pre-treated patients with advanced ccRCC, and was recently approved for the treatment of cancers associated with VHL disease [32, 33]. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.