Casdatifan (HIF-2α) + cabozantinib logs 41% ORR in previously treated clear-cell RCC

Casdatifan, an oral hypoxia-inducible-factor-2α inhibitor, combined with cabozantinib (VEGFR-TKI) in the Phase 1 ARC-20 expansion (NCT05536141). Twenty-seven adults with IO-exposed ± VEGFR-TKI clear-cell RCC received casdatifan 100 mg QD plus cabozantinib 60 mg QD; median follow-up was 2.9 months. Among 22 efficacy-evaluable patients, ORR reached 41% (1 CR, 8 PR) and activity spanned all IMDC risk groups. 89% of patients experienced side effects (any-grade). Common grade ≥3 TRAEs included anemia (26%) and hypoxia (11%). Only one patient discontinued treatment due to TRAEs (4%). This early ORR roughly doubles the 15–19% seen with cabozantinib monotherapy post-VEGF blockade and trails the 57% reported for belzutifan + cabozantinib in renal cell carcinoma, yet the grade ≥3 AE rate (≈30%) is more tolerable than the ≥54% in that Phase 2 combo.