Casdatifan (HIF-2α inhibitor) drives 31–35% ORR with ~12.2-mo PFS in refractory metastatic ccRCC

Casdatifan is an orally bioavailable, potent and selective small-molecule HIF-2α inhibitor evaluated as monotherapy in the ARC-20 dose-expansion study (NCT05536141) in refractory metastatic clear cell renal cell carcinoma (100mg QD cohort n=32; total n=127). Confirmed ORR was 35% (95% CI 19–55) at 100mg QD and 31% (95% CI 23–40) overall; median PFS was not estimable in the 100mg QD cohort (95% CI 5.7–NE) and 12.2 months (95% CI 9.4–20.6) overall—numerically above typical post–IO+VEGFR-TKI single-agent benchmarks like cabozantinib in METEOR (median PFS 7.4 months) and far above everolimus (median PFS 3.8 months). Safety looked “class-consistent” for HIF-2α inhibition (anemia, hypoxia), with casdatifan-related discontinuations infrequent (3%); depth of serum erythropoietin (EPO) suppression correlated with better outcomes (higher ORR, fewer PD events, longer PFS), and tumor EPO/HIF-2α signatures tracked with clinical benefit.