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

Introduction: Recently, casdatifan (Cas), an orally bioavailable small molecule inhibitor of hypoxia-inducible factor-2 alpha (HIF-2alpha), 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-2alpha transcriptional signatures (Courtney et al., CCR 2020), and clinical benefit from HIF-2alpha inhibitors has not been investigated. Herein we explore whether patients characterized by these RNA-based molecular subtypes show evidence of HIF-2alpha 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 (χ 2 =0.26, p=0.878; Log-rank p>0.9). We further explored the relationship between HIF-2alpha activity and previously defined ccRCC subtypes using HIF-2alpha-related gene expression signatures; there was no enrichment of HIF-2alpha related gene expression signatures in these predefined molecular categories. However, we observed a strong relationship between the expression of HIF-2alpha transcriptional signatures and clinical benefit in patients treated with Cas monotherapy. In contrast, higher HIF-2alpha gene signature expression was associated with shorter PFS in patients treated with either sunitinib (Log-rank, p<0.001) or atezolizumab plus bevacizumab (Log-rank p=0.012) in available data from the IMmotion 151 study. Conclusions: The HIF-2alpha 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-2alpha transcriptional signatures in tumor samples.