Abstract A023: Erythropoietin (EPO) is a Pharmacodynamic Biomarker for Systemic HIF-2α Inhibition that Correlates with the Clinical Activity of Casdatifan

Abstract Background: Dysregulation of hypoxia-inducible factor 2-alpha (HIF-2α) in clear-cell renal cell carcinoma (ccRCC) contributes to increased angiogenesis, proliferation, and cancer cell survival. Casdatifan (Cas) is an orally bioavailable small-molecule HIF-2α inhibitor that has shown promising efficacy in metastatic ccRCC in the ARC-20 phase 1 trial (NCT05536141). Erythropoietin (EPO) is a known HIF-2α transcription target, and serum EPO (sEPO) levels decrease after treatment with HIF-2α inhibitors. However, the relationship between EPO expression in ccRCC patients, HIF-2α inhibitor-induced changes and clinical benefit has not been studied. Here we investigated baseline and longitudinal sEPO levels and tumor EPO expression in ARC-20 as potential biomarkers for systemic HIF-2α inhibition and explored their association with clinical benefit of Cas. Methods: The biomarker-evaluable population (BEP) was comprised of 127 patients evaluable for overall response (as of 3/14/25) and enrolled in the 50-200mg Cas monotherapy dose escalation and expansion cohorts. sEPO was measured by immunoassay; tumor EPO mRNA was quantified by RNAseq. Results: Baseline sEPO levels from BEP were significantly higher than healthy volunteers (P<0.0001) and above the normal sEPO range (>18.5mIU/ml) in 49% (62/127) of BEP. Following Cas treatment, sEPO levels decreased as early as 4hr after the first dose and reached maximal suppression between day 8 and day 22 on treatment. Deep sEPO reductions were observed at all Cas dose levels and sustained throughout the course of treatment. Some patients experienced a slight sEPO rebound to ∼ -60% of baseline levels at 12-week post-treatment, following which sEPO suppression was maintained for the duration of treatment. The maximum sEPO decreases for the 100mg QD (n=28) cohort ranged from -99% to -47%. In 2 pairs of matched pre-/post-treatment biopsies, expression of tumor EPO and HIF-2α transcription target genes, SERPINE1 and PTHLH, were downregulated 2 to 61-fold after Cas treatment. Patients with an objective response had significantly deeper maximum sEPO reduction on treatment compared to patients with progressive disease (PD) as their best overall response (P<0.001). Consistently, patients with a deeper (by median, -85%) maximum sEPO reduction had a higher overall response rate (ORR) (37.5%) and a lower primary PD rate (7.8%) than those with less deep sEPO reductions (ORR: 17.5%; PD: 23.8%), indicating a strong association between depth of sEPO reduction and clinical benefit. Furthermore, among patients with elevated (>18.5mIU/ml) baseline sEPO levels, only 1/14 (7%) with high tumor EPO expression experienced primary PD on Cas compared to 4/12 (33%) cases with low tumor EPO expression. Conclusions: sEPO may provide a window into systemic HIF-2α inhibition in ccRCC patients. Cas monotherapy resulted in deep and sustained reductions of sEPO, as well as a significant downregulation of tumor EPO and other HIF-2α target genes. Depth of sEPO reduction and tumor EPO expression were strongly associated with clinical benefit for Cas. Citation Format: Yinghui Guan, Ben Weeder, Amita Patnaik, Moshe Ornstein, Benjamin Garmezy, Alexandra Drakaki, Brian Rini, Jamie Merchan, Sun Young Rha, Ralph Hauke, Rohit Kumar, Pedro Barata, Craig Gedye, Che-Kai Tsao, Jae Lyun. Lee, Yusra Shao, Se Hoon. Park, Marc Matrana, Clara Hwang, Hunter Cole, Chris Negro, Paul Foster, Mohammad Ghasemi, Jianfen Chen, Toni Choueiri, Sean Cho, Omar Kabbarah. Erythropoietin (EPO) is a Pharmacodynamic Biomarker for Systemic HIF-2α Inhibition that Correlates with the Clinical Activity of Casdatifan [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A023.