Abstract PR006: Evidence for the involvement of HIF-2α biology in the clinical efficacy of casdatifan, a novel HIF-2α inhibitor, in clear cell renal cell carcinoma (ccRCC)

Abstract Background: Dysregulation of the VHL pathway leads to HIF-2α accumulation and upregulation of multiple oncogenic pathways that drive ccRCC, the most common form of renal cancer. Casdatifan is an orally bioavailable and potent HIF-2α inhibitor that has demonstrated robust clinical activity in the ARC-20 clinical trial (NCT05536141). Here we present clinical biomarker and biological findings from ARC-20 patient blood and tumor tissue that illustrate the relationship between the clinical benefit of casdatifan and the level of tumor HIF-2α activation. Methods: Serum levels of HIF-2α-regulated erythropoietin (sEPO) were measured (at baseline and on treatment) in 129 ccRCC patients treated with casdatifan monotherapy with available clinical outcomes data. Transcriptome sequencing on tumor tissue was carried out on 67 ccRCC cases to assess tumor EPO mRNA and molecular pathway signaling by gene set enrichment analysis (GSEA). HIF-2α protein levels were quantified by immunohistochemistry in 66 of these cases. Results: Patients who exhibited deeper-than-the-median (>85%) on-treatment sEPO reductions were more likely to experience a response (44.6% vs. 20.3%), less likely to experience rapid PD (9.2% vs. 26.6%), and had improved PFS compared to patients with less-than-the-median (<85%) sEPO reductions, with a mPFS of 14.6 (10.9, 22.8) vs. 9.6 months (4.1, 17.5), respectively. Tumors from patients who exhibited PD on casdatifan monotherapy expressed significantly lower levels of EPO mRNA compared to tumors from patients who did not experience rapid progression (p <0.01). Notably, patients with high levels of tumor EPO mRNA consistently experienced deep sEPO reduction with casdatifan. HIF-2α-dependent tumors from patients who did not experience rapid progression (non-PD) displayed transcriptional signatures consistent with engagement of multiple HIF-2α-regulated biological pathways, including hypoxia and HIF-2α-driven gene expression signatures, whereas pathways such as oxidative phosphorylation were enriched in the tumors from patients with PD. Overall, patients (51/66) whose tumors expressed high levels of HIF-2α by IHC experienced significantly improved PFS compared to those (15/66) with low HIF-2α protein levels (p = 0.006). Notably, HIF-2α protein expression was correlated with the HIF-2α-driven gene expression signature by Courtney et al. (p =0.003). Assessment of this HIF-2α signature revealed a correlation with PFS (cases with high signature expression compared to low expression, p=0.045). Conclusions: These data indicate that a majority (∼80%) of advanced ccRCC tumors have high levels of HIF-2α and HIF-2α-dependent biological pathways and respond favorably to casdatifan monotherapy. Citation Format: Jonathan Yingling, Yinghui Guan, Benjamin Weeder, Jasrikat Singh, Brian Rini, Soonweng Cho, Angelo Kaplan, Omar Kabbarah, Toni K. Choueiri. Evidence for the involvement of HIF-2α biology in the clinical efficacy of casdatifan, a novel HIF-2α inhibitor, in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR006.