Disproportionality Analysis of Gastrointestinal Adverse Events Associated With Trastuzumab Deruxtecan Using the Japanese Adverse Drug Event Report database

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Abstract
Background/Aim: This study aimed to evaluate the disproportionality, times to onset, incidence rates, and outcomes of gastrointestinal adverse events (AEs) associated with trastuzumab deruxtecan (T-DXd), using data from the Japanese Adverse Drug Event Report database (JADER). Patients and Methods: We analyzed data for the period from April 2004 to December 2024. Those on gastrointestinal AEs were extracted and the disproportionality of T-DXd-associated AEs was assessed by calculating reporting odds ratios (RORs). Results: Of the 3,221,393 reports analyzed, we identified 1,561 reports of AEs associated with T-DXd, including 264 gastrointestinal AEs. Signals were detected for seven gastrointestinal AEs: nausea, decreased appetite, vomiting, diarrhoea, ascites, dehydration, and enterocolitis. Fatal outcomes were reported for six of these events, excluding ascites, with particularly high fatality rates observed for diarrhoea, dehydration, and enterocolitis. A histogram of median times to onset indicated that gastrointestinal AEs associated with T-DXd occurred 3 to 84 days after administration. Weibull distributions showed that nausea, decreased appetite, and vomiting occurred constantly throughout the exposure period (random failure type), and diarrhoea and dehydration developed in a dose-dependent manner (wear-out failure-type). Conclusion: Gastrointestinal adverse events associated with T-DXd can arise early or later in treatment and may lead to serious or fatal outcomes. These findings underscore the importance of continuous post-marketing surveillance and proactive clinical management to detect and mitigate these potentially severe AEs.

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