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

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.

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.

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.

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.