Adverse Event Profiling and Comparative Analysis of HER2-targeting Antibody-drug Conjugates Using Pharmacovigilance...

Anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates have incompletely characterized safety profiles. Therefore, we compared the adverse events for trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) using the Japanese Adverse Drug Event Report (JADER) database and U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

We analyzed the JADER (April 2004-April 2025) and FAERS (Q1 1997-Q1 2025) databases for the target drugs T-DM1 and T-DXd, with trastuzumab and pertuzumab as comparators. All reported cases were included regardless of severity grade.

Hepatobiliary disorder signals were detected for T-DM1, whereas hematotoxicity- and infection-related signals were prominent for T-DXd, including sepsis and Pneumocystis jirovecii pneumonia (PJP). Interstitial lung disease was observed for both agents. Signals for cardiac disorders were detected for trastuzumab, pertuzumab and T-DM1, but not for T-DXd. T-DXd-associated nausea and myelosuppression were frequently reported within 40 days of treatment initiation, whereas PJP was reported later, with a median time to onset of 90 days.

Analyses using JADER and FAERS revealed the adverse event profiles of HER2 antibody-drug conjugates. Hepatobiliary disorders were characteristic of T-DM1, whereas hematotoxicity and infection-related events were characteristic of T-DXd. Interstitial lung disease was detected for both agents. These findings were consistent with those of clinical trials. Infection-related events associated with T-DXd were identified as potential signals, highlighting the clinical relevance of PJP, with a median time to onset of approximately 90 days.