A real-world pharmacovigilance study of belzutifan in renal cell carcinoma and von Hippel-Lindau disease: insights from the FDA adverse event reporting system database.

Background: Belzutifan, a first-in-class HIF-2α inhibitor, has been approved for von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and previously treated sporadic RCC. While its safety profile has been characterized in LITESPARK clinical trials, real-world pharmacovigilance data remain limited.

Aim: This study evaluated the characteristics (including frequency, system-specific toxicities, and time-to-onset) of real-world belzutifan-associated adverse events (AEs), aiming to identify emerging safety signals, and assessing potential disease progression-related AEs using data from the FDA Adverse Event Reporting System (FAERS).

Method: FAERS reports related to belzutifan were retrieved for the period Q1 2004 to Q4 2024. Duplicate reports and those flagged for deletion were excluded. Disproportionality analysis was conducted using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and the Medicines and Healthcare Products Regulatory Agency (MHRA) method to identify significant safety signals. Time-to-onset analysis was performed to assess adverse event (AE) occurrence patterns.

Results: A total of 248 AE reports were identified, with an increasing trend following FDA approvals in 2021 and 2023. The most frequently reported AEs were anemia (ROR: 19.00, 95% CI 13.51-26.73) and hypoxia (ROR: 59.48, 95% CI 38.09-92.88), consistent with clinical trial data. Significant signals for neurological (brain fog), hepatic (liver injury), metabolic (hypocalcemia), and respiratory (pneumonia) AEs were also observed. Reports of disease progression-related AEs were also prominent. A majority (71.1%) of AEs occurred within the first 6 months of treatment initiation, suggesting the need for early monitoring.

Conclusion: This study provided the first real-world pharmacovigilance assessment of belzutifan, confirming expected AEs while identifying emerging safety signals. Close monitoring of hematologic, respiratory, hepatic, and neurological toxicities is warranted. Further prospective studies are needed to optimize patient selection and improve AE management.