Real-world pharmacovigilance assessment of hepatotoxicity risk with HER2-Targeted drugs using FAERS database analysis

Human epidermal growth factor receptor 2 (HER2)-targeted therapies, including monoclonal antibodies (mAbs), small-molecule tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs), have significantly improved clinical outcomes in HER2-positive cancers. However, hepatotoxicity remains a major concern with these therapies, and a comprehensive analysis of the hepatotoxicity signals across different HER2-targeted drugs is lacking. We aim to conduct a comprehensive comparative analysis of hepatotoxicity risk related to various HER2-targeted agents. Real-world pharmacovigilance research was conducted on the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from Q1 2012 to Q2 2024. Disproportionality analysis was used to assess the strength of hepatotoxicity signals for trastuzumab, pertuzumab, T-DM1, T-DXd, and TKIs. Reporting Odds Ratios (ROR) was calculated to identify significant hepatotoxicity signals. Moreover, the time to onset (TTO) of hepatotoxicity was also evaluated. A total of 2,986 hepatotoxicity cases concerning HER2-targeted agents were collected. The strongest hepatotoxicity signal was found with T-DM1, yielding an ROR of 6.00 (95% CI: 5.51-6.54), followed by trastuzumab with an ROR of 2.65 (95% CI: 2.52-2.79) and T-DXd with an ROR of 2.51 (95% CI: 2.25-2.80). TKIs showed an ROR of 2.36 (95% CI: 2.11-2.64), while pertuzumab demonstrated the lowest signal with an ROR of 1.73 (95% CI: 1.54-1.94). The liver toxicity of HER2-targeted drugs primarily manifests as elevated ALT, AST, and bilirubin levels. Additionally, T-DM1 can lead to hepatic coma and elevated ALP levels, while T-DXd may cause liver failure and jaundice. Besides, pertuzumab showed the shortest median TTO (21 days, interquartile range [IQR] 8-98), and trastuzumab as the longest (210 days, IQR 7-656). This study identifies significant hepatotoxicity signals associated with HER2-targeted therapies, highlights the need for regular and long-term assessment of liver enzymes and bilirubin monitoring. Despite the hepatotoxicity risks, HER2-targeted therapies remain vital in the treatment of HER2-positive cancers, requiring careful management to balance efficacy and safety.