Abstract A034: HIF-2-mediated gene expression is highest in metastatic and cluster-exclude clear cell renal cell carcinoma tumors

Introduction: Hypoxia inducible factor (HIF)-2 inhibitors are FDA-approved for the treatment of metastatic clear cell renal cell carcinoma (ccRCC). In theory, all ccRCC tumors should exhibit HIF-2 stabilization due to VHL silencing. However, many patients fail to respond to HIF-2 inhibitors. A biomarker to identify patients most likely to respond to HIF-2 inhibitors is needed. Methods: In this analysis, we explored a HIF-2 gene expression signature (Courtney et al., Clinical Cancer Research 2020) in two independent cohorts of patients with metastatic ccRCC. The two cohorts include a discovery multi-institutional cohort from VUMC, UTSW, and Rutgers that includes 205 tumor samples, including 12 matched primary:metastatic pairs. As a validation cohort, we utilized samples from the prospective phase 2 OPTIC RCC trial (NCT05361720), which includes 95 samples and 23 matched primary:metastatic pairs. Results: In the discovery cohort, the HIF-2 gene expression signature was higher in metastatic tumors than in primary tumors (p<0.01). Likewise, 75% of matched primary:metastatic pairs showed higher expression in the metastatic tumor (p<0.05). When examining the OPTIC RCC gene expression signatures, we observed higher levels of the HIF-2 gene expression signature in cluster_Exclude tumors compared with cluster_Angio or cluster_IO tumors (p<0.01). In the OPTIC RCC validation cohort, we observed similar trends, including higher expression of the HIF-2 gene expression signature in metastatic tumors from matched primary:metastatic pairs (p<0.05) and in cluster_Exclude relative to cluster_Angio tumors (p<0.01). We will also identify OPTIC RCC patients with high expression of the HIF-2 gene expression signature and assess their response to approved regimens for previously untreated ccRCC, including ipilimumab plus nivolumab and cabozantinib plus nivolumab. Conclusion: Metastatic tumors exhibit higher expression of a HIF-2 gene expression signature relative to primary tumors. In addition, the OPTIC RCC cluster_Exclude tumors have the highest levels of HIF-2 gene expression signatures, a group of tumors that have a poor overall prognosis. Citation Format: Scott M. Haake, Katy Beckermann, Alex Nesta, Eric Davis, Pedro C. Barata, Moshe C. Ornstein, Nataliya Mar, Ellen Heimann-Nichols, Tian Zhang, James Brugarolas, Anupama Reddy, Brian I. Rini. HIF-2-mediated gene expression is highest in metastatic and cluster-exclude clear cell renal cell carcinoma tumors [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 A034.