Real-world outcomes of clear-cell renal cell carcinoma (ccRCC) patients treated with belzutifan stratified by von Hippel-Lindau (VHL) status.

475 Background: Belzutifan is a HIF-2a inhibitor with demonstrated efficacy in ccRCC associated with VHL syndrome. Belzutifan was also recently approved for sporadic advanced ccRCC after PD-1/PD-L1 inhibitor and VEGF-TKI therapy following the positive LITESPARK-005 trial. VHL inactivation results in constitutive activation of HIF-2a in VHL syndrome and also in sporadic ccRCC, providing clear mechanistic rationale for belzutifan. To date, no real-world data on belzutifan treatment correlated with genomic findings have been presented. We hypothesize that ccRCC patients with somatic alterations in VHL will experience superior response to belzutifan. Methods: Veterans included in the central cancer registry (VACCR) were queried for somatic tumor testing within the National Precision Oncology Program (NPOP) and treatment was obtained from VINCI (Veterans INformatics and Computing Infrastructure). Genomic results from commercial NGS assays were used to identify VHL alterations of any type. The Kaplan-Meier method was used to determine overall survival and time on treatment, defined as initial dispense of belzutifan to last dispense. Results: One-hundred nineteen (119) patients (pts) met inclusion criteria and were selected for analysis. Pts were predominantly male (116/119, 97.5%). Median age at initiation of belzutifan was 72.5 years. Median follow-up from initiation of belzutifan was 218 days (range 8 - 1431 days). Overall survival data (OS) were available for all patients. Genomic results were available for 39/119 pts (32.8%). Of these, VHL alterations were present in 30/39 pts (76.9%). Median time on treatment (TT) was 107 days (112 days for pts w/ genomic results). Median OS was 484 days (356 days for pts w/ genomic results). Among evaluable pts, median OS was 96 days when VHL alteration was absent and 484 days when VHL alteration was present (K-M p = 0.17). TT was 95 days when VHL alteration was absent and 113 days when VHL alteration was present (K-M p = 0.41). Conclusions: In this study of Veterans with ccRCC treated with belzutifan, pts with somatic VHL alterations may respond more favorably to belzutifan compared to pts without VHL alteration. A trend towards improved OS and time on treatment was seen in this cohort, but did not reach statistical significance. Further study is warranted to determine the benefit of belzutifan in ccRCC patients with somatic VHL alterations, as well as identify additional genomic correlates which may assist in patient selection or risk stratification.