Casdatifan (HIF-2α inhibitor) Monotherapy in Late-Line ccRCC Shows Class-On-Target Anemia/Hypoxia With Low Discontinuation

Casdatifan is a potent, selective oral hypoxia-inducible factor-2α (HIF-2α) inhibitor evaluated as monotherapy in the ongoing ARC-20 platform study (NCT05536141) in metastatic clear cell RCC previously treated with anti–PD-(L)1 and VEGFR-TKI and naïve to HIF-2α inhibition. This pooled safety analysis used an August 15, 2025 data cutoff and included the ARC-20 100-mg once-daily cohort (n=32), using the dose selected for study in the Phase 3 PEAK-1 trial, plus a pooled late-line monotherapy population across 50-mg QD, 50-mg BID, 100-mg QD, and 150-mg QD dosing (n=127). Any TEAE occurred in 97%–98% and grade ≥3 TEAEs in 50%–60%; TRAEs drove dose reductions in 22%–24% (most commonly anemia 9%–14%, fatigue 4%–6%, hypoxia 3%–7%) and TRAE-related discontinuation was 3% in both datasets, with no treatment-related deaths. On-target toxicity was dominated by anemia (treatment-related any-grade 84%–89%; grade ≥3 25% at 100mg QD and 41% pooled) and hypoxia (5/32 and 23/127 with hypoxia from any cause; 70%–80% required temporary supplemental oxygen); notably, anemia led to treatment interruption in 28%–35% but no discontinuations, and exploratory efficacy-by-management showed longer mPFS with ESA-only support (21.7 months; n=47) vs transfusion use (9.4 months; n=33), though this comparison is intrinsically confounded by anemia severity and clinical selection. For context in this post–IO/VEGFR-TKI setting, belzutifan (the approved HIF-2α inhibitor) in LITESPARK-005 reported mPFS ~5.6 months (vs everolimus ~5.6 months; HR 0.75), underscoring that anemia/hypoxia are expected class effects while durable disease control is the differentiation bar.