Abstract 7898: Clinical benefit of the HIF-2α inhibitor casdatifan (Cas) across molecular subtypes in clear cell renal cell carcinoma (ccRCC) patients from the ARC-20 Clinical Study

Abstract Introduction: Recently, casdatifan (Cas), an orally bioavailable small molecule inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α), demonstrated promising efficacy in metastatic ccRCC in the ARC-20 clinical trial (NCT05536141). Despite progress towards the identification of ccRCC molecular subtypes, the relationship between established molecular classifications (Motzer et al., Cancer Cell 2020), HIF-2α transcriptional signatures (Courtney et al., CCR 2020), and clinical benefit from HIF-2α inhibitors has not been investigated. Herein we explore whether patients characterized by these RNA-based molecular subtypes show evidence of HIF-2α activity and whether they derive clinical benefit from Cas monotherapy. Methods: Archival tumor biopsies were taken from 67 ccRCC patients enrolled in ARC-20 who received daily doses ≥50mg of Cas monotherapy. Molecular subtypes were defined based on the quantile normalized RNA expression of literature-defined molecular signatures. Gene signature assessment across subtypes was performed using ssGSEA on voom-normalized RNA expression levels. Results: Using literature-based classification of ARC-20 samples, patients were assigned to one of six molecular subtypes (angiogenesis/stromal, angiogenesis, immune/proliferative, proliferative, stromal/proliferative, or unclassified), falling into one of three broader molecular categories (angiogenesis, immune, or other). Cas monotherapy resulted in similar disease control rate (DCR) and progression free survival (PFS) across the previously derived molecular subtypes (𝓧;;2=0.26, p=0.878; Log-rank p0.9). We further explored the relationship between HIF-2α activity and previously defined ccRCC subtypes using HIF-2α-related gene expression signatures; there was no enrichment of HIF-2α related gene expression signatures in these predefined molecular categories. However, we observed a strong relationship between the expression of HIF-2α transcriptional signatures and clinical benefit in patients treated with Cas monotherapy. In contrast, higher HIF-2α gene signature expression was associated with shorter PFS in patients treated with either sunitinib (Log-rank, p0.001) or atezolizumab plus bevacizumab (Log-rank p=0.012) in available data from the IMmotion 151 study. Conclusions: The HIF-2α inhibitor Cas produces similar clinical benefit in all previously described molecular subtypes of ccRCC. While most ARC-20 patients derived benefit from Cas monotherapy, there was a strong relationship between clinical benefit (PFS) and expression levels of HIF-2α transcriptional signatures in tumor samples. Citation Format: Benjamin Weeder, Yinghui Guan, Jaskirat Singh, Brian Rini, Toni K. Choueiri, Angelo Kaplan, Omar Kabbarah, Soonweng Cho. Clinical benefit of the HIF-2α inhibitor casdatifan (Cas) across molecular subtypes in clear cell renal cell carcinoma (ccRCC) patients from the ARC-20 Clinical Study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7898.