Real-World Effectiveness and Tolerability of Belzutifan in Sporadic Clear Cell Renal Cell Carcinoma: A Retrospective Cohort Study With Exploratory Genomic Correlation

Background Belzutifan, a hypoxia-inducible factor 2α (HIF-2α) inhibitor, is approved for advanced clear cell renal cell carcinoma (ccRCC) after immune checkpoint and antiangiogenic therapy, but real-world evidence is limited and no prior real-world study has correlated outcomes with tumor genomics. We evaluated real-world effectiveness, tolerability, and genomic correlates of belzutifan in sporadic ccRCC. Patients and Methods We retrospectively identified patients with sporadic ccRCC who received belzutifan at Washington University / Siteman Cancer Center between 01/01/2021 and 04/01/2026. Best response was investigator-assessed from routine clinical radiology using RECIST 1.1 categories. Response was reported for the full treated cohort (N = 88; intention-to-treat-like) and for the RECIST-evaluable subset (n = 75). Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier methods from belzutifan initiation; associations with somatic VHL, PBRM1, BAP1, and SETD2 status were explored. A germline VHL syndrome cohort was described separately. Results Among 88 patients (median age 66 years; 70% male; among 78 with documented prior therapy, 88% prior immune checkpoint inhibitor and 94% prior VEGFR-TKI), the objective response rate was 33.0% (95% CI, 23.3-43.8) in the full cohort and 38.7% among 75 evaluable patients, and the disease control rate was 54.5% (95% CI, 43.6-65.2) and 64.0%, respectively. Median PFS was 8.8 months (95% CI, 4.1-15.5) and median OS was not reached (95% CI, 21.3-not reached) after a median follow-up of 16.1 months. PFS did not differ significantly by somatic VHL status (11.0 vs 3.2 months; HR 0.59; P = .22) or other 3p genes. The most common adverse events were anemia (71.6%; 29.5% grade ≥3) and hypoxia (18.2%; 10.2% grade ≥3); 5.6% discontinued for toxicity and there were no treatment-related deaths. Conclusion In the largest real-world cohort of sporadic ccRCC treated with belzutifan reported to date, effectiveness and safety were consistent with registrational data in a broader, more representative population. We did not detect significant differences across chromosome 3p genomic subgroups; these exploratory analyses were underpowered and should not be interpreted as evidence of no biomarker effect. Micro Abstract Real-world data for belzutifan in sporadic clear cell renal cell carcinoma are limited to a single small cohort. In this retrospective study of 88 heavily pretreated patients, belzutifan produced an objective response rate of 33.0% and a median progression-free survival of 8.8 months, with a tolerable, on-mechanism safety profile. Outcomes were consistent across VHL and chromosome 3p genomic subgroups.