Sex-Specific Adverse Events and Cardiovascular Toxicity of Cabozantinib in Renal Cell Carcinoma: A Nine-Year Pharmacovigilance Study.

BACKGROUND

Cabozantinib is a multi-target tyrosine kinase inhibitor widely used in advanced renal cell carcinoma (RCC). However, real-world evidence regarding its safety profile, particularly sex-specific adverse events (AEs) and cardiovascular toxicity, remains limited.

METHODS

A retrospective pharmacovigilance study was performed using data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from Q2 2016 to Q2 2025. Reports listing cabozantinib as the primary suspected drug and RCC as the indication were included. Disproportionality analyses using Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) were conducted to identify safety signals. Sex-specific differences were evaluated using a modified 2 × 2 contingency table. Time-to-onset (TTO) was assessed with Weibull distribution modeling. Cardiovascular toxicity was further analyzed using standardized MedDRA queries (SMQs) and compared with sunitinib.

RESULTS

A total of 22,778 cabozantinib-related AE reports were identified, with a male-to-female ratio of 2.41:1 and a median age of 65 years. Major safety signals involved gastrointestinal, endocrine, and metabolic disorders, with strong associations observed for palmar-plantar erythrodysesthesia syndrome, stomatitis, oral pain, and taste disturbance. The median TTO was 40 days, with a Weibull shape parameter β < 1, indicating an early-onset pattern. Females showed higher reporting of gastrointestinal and dermatologic AEs, while males had higher frequencies of severe outcomes, including acute myocardial infarction. Cabozantinib demonstrated a lower overall cardiovascular AE signal (ROR = 0.70, 95% CI: 0.66-0.75) compared with sunitinib (ROR = 0.87, 95% CI: 0.82-0.91).

CONCLUSIONS

This real-world study highlights sex-specific safety differences, early AE onset, and a comparatively favorable cardiovascular profile of cabozantinib, supporting individualized monitoring strategies in RCC treatment.