Genomic and clinical correlates of belzutifan treatment in renal cell carcinoma (RCC): A retrospective analysis of 150 RCC patients.

4541 Background: Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor approved for RCC that targets a central driver in RCC pathogenesis; however, predictive biomarkers of response remain poorly defined. Methods: Comprehensive DNA (592-gene panel or whole exome) and RNA (whole transcriptome) sequencing were performed by Caris Life Sciences on RCC samples. Clear cell RCC and RCC-NOS with VHL mutations were included. Belzutifan time on treatment (ToT) was derived from insurance claims, and patients were classified as responders or non-responders using the median ToT. Results: A total of 150 belzutifan-treated RCC tumors were included in the analysis, of which 29% were primary kidney tumors and the remainder were from metastatic sites. The study population was classified as responders (n=57) or non-responders (n=93) using a median time on treatment of 85 days (95% CI: 71–114). Baseline characteristics were similar, except responders were younger (median age 57 vs 64 years, p=0.007). Transcriptomic analysis showed similar HIF-2α (median 7.78 vs 7.61) and CA9 (4.82 vs 4.54) expression between responders and non-responders without statistical significance. Responders showed enrichment of PTEN (15.8% vs. 3.3%, p=0.03) and PIK3R1 alterations (7.0% vs. 0.0%, p=0.04). Responders demonstrated numerically higher frequencies of PBRM1 (54.4% vs. 44.3%, p=0.46) and PIK3CA mutations (8.8% vs. 3.3%, p=0.24). Alterations in DNA damage response genes were also numerically more common among responders, including TP53 (14.0% vs. 4.9%, p=0.11) and ATM (3.5% vs. 1.6%, p=0.56), although none of these differences reached statistical significance. In contrast, non-responders exhibited numerically higher frequencies of BAP1 (18.0% vs. 8.8%, p=0.10), SETD2 (26.2% vs. 19.3%, p=0.27), and ARID1A (5.1% vs. 1.8%, p=0.30), all of which were also not statistically significant. Conclusions: HIF2-α RNA expression alone does not predict belzutifan response in RCC. Responders demonstrated alterations in PBRM1, PI3K/AKT/mTOR, and DNA damage response genes, while non-responders showed numerically higher frequencies of chromatin remodeling mutations including BAP1 and SETD2. Study limitation included small sample size and short follow-up. Larger datasets are required to validate these findings.