Real-world overall survival outcomes of belzutifan treatment in advanced renal cell carcinoma.

4561 Background: Belzutifan, a hypoxia-inducible factor–2α inhibitor, is an emerging therapy for advanced renal cell carcinoma (RCC) that demonstrated significant benefit over everolimus in the LITESPARK-005 trial. We aimed to validate these findings in a real-world setting and identify clinical prognostic factors within a large, multi-institutional cohort. Methods: We conducted a retrospective cohort study, using Epic Cosmos, of adults with RCC who initiated Belzutifan on or after the FDA Approval date (December 14, 2023) to Dec 20, 2025, ensuring at least one month of follow-up prior to the query date. Overall survival (OS) was measured from the treatment start date to death, with censoring at the last clinical encounter. Survival was estimated using Kaplan–Meier methods. Associations between baseline clinical and laboratory variables and OS were evaluated using univariable Cox proportional hazards models with false discovery rate (FDR) correction. Results: A total of 2,844 patients were included; the median age was 66 years, 72% were male, and 51.2% had documented tobacco use. The OS probabilities were 80.9%, 68.1%, 58.3%, and 53.2% at 6, 12, 18, and 24 months, respectively, and comparable to the LITESPARK-005 trial. Among clinical variables, tobacco use was associated with worse survival (HR 1.24 95% CI 1.08–1.44, FDR = 0.014), whereas female sex (HR 0.78 0.66–0.92, FDR = 0.014) and higher BMI (HR 0.96 0.95–0.98, FDR <0.001) were associated with improved outcomes. Markers of nutritional and hematologic reserve were strongly protective, including higher Albumin (HR 0.46 0.41–0.52, FDR <0.001), Total Protein (HR 0.77 0.70–0.89, FDR <0.001), Hemoglobin (HR 0.90 0.87–0.93, FDR <0.001), RBC (HR 0.69 0.62–0.75, FDR <0.001), and MPV (HR 0.90 0.84–0.96, FDR = 0.002). Inflammatory and immune markers demonstrated divergent effects: higher Lymphocytes (HR 0.53 0.46–0.61, FDR <0.001) and Lymphocyte-to-Monocyte Ratio (HR 0.75 0.71–0.80, FDR <0.001) predicted favorable outcomes. Conversely, worse survival was associated with elevated RDW (HR 1.14 1.11–1.17, FDR <0.001), Monocytes (HR 1.71 1.34–2.20, FDR <0.001), Basophil-to-Lymphocyte Ratio (HR 2.39 1.20–4.77, FDR = 0.019) and Neutrophils (HR 1.06 1.04–1.07, FDR <0.001),.Higher Corrected Calcium (HR 1.43 1.30–1.57, FDR <0.001) and Total Bilirubin (HR 1.13 1.04–1.22, FDR = 0.005) were associated with inferior outcomes. Conclusions: In the largest real-world cohort to date, overall survival after belzutifan initiation mirrored LITESPARK-005, supporting its effectiveness in routine practice. Baseline nutritional, hematologic, and immune markers were associated with improved survival, while systemic inflammation and metabolic dysfunction predicted worse outcomes, highlighting the prognostic value of routine clinical variables.