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 none has correlated outcomes with tumor genomics. We evaluated effectiveness, tolerability, and genomic correlates in sporadic ccRCC. PATIENTS AND METHODS:We retrospectively identified patients with sporadic ccRCC treated with belzutifan between January 2021 and April 2026. Best response was investigator-assessed from routine radiology using RECIST 1.1 and reported for the full treated cohort (N = 88) and the evaluable subset (n = 75). Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier from 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; of 78 with prior therapy, 88% prior immune checkpoint inhibitor, 94% prior VEGFR-TKI), objective response rate was 33.0% (95% CI, 23.3-43.8) overall and 38.7% among evaluable patients; disease control rate was 54.5% and 64.0%, respectively. Median PFS was 8.8 months (95% CI, 4.1-15.5); median OS was not reached after 16.1 months median follow-up. PFS did not differ 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, with no treatment-related deaths. CONCLUSION:In the largest real-world sporadic ccRCC cohort treated with belzutifan to date, effectiveness and safety were consistent with registrational data in a broader, more representative population. Exploratory chromosome 3p analyses showed no significant differences but were underpowered.