Introduction: Metastatic breast cancer (MBC) remains a major clinical challenge despite recent advances in HER2-targeted therapies such as trastuzumab deruxtecan (T-DXd). While clinical trials have demonstrated its efficacy, concerns about treatment-emergent toxicities persist, highlighting the need for real-world pharmacovigilance to capture a broader spectrum of adverse events (AEs). Methods: We analyzed reports from the US FDA Adverse Event Reporting System (FAERS, 2004–2024), including trastuzumab deruxtecan reports recorded since its market introduction in 2019. Disproportionality analyses were performed to identify potential AE signals. Time-to-onset distributions were assessed, and a clinical prioritization score was developed to rank AEs based on signal strength, frequency, mortality, and classification as important or designated medical events. Results: Disproportionality analyses revealed significant AE signals associated with T-DXd across multiple organ systems, including injury and procedural complications, respiratory, gastrointestinal, and social circumstances. Time-to-onset analysis revealed substantial heterogeneity in the timing of T-DXd–associated AEs. Early-onset events included dyspnea and eye disorders, whereas cardiac and nervous system toxicities showed delayed onset. Among twelve high-priority AEs, peritonitis received the highest priority scores (scores = 11). Interstitial lung disease demonstrated the most prominent disproportionality signal. Several other pulmonary-related events, including pneumonitis, pulmonary fibrosis, and pulmonary toxicity, also ranked as high priority. Conclusion: This study highlights respiratory and gastrointestinal toxicities as major risks associated with T-DXd in metastatic breast cancer. Careful monitoring, early intervention, and patient education are essential to balance benefits and risks, while future research should focus on molecular mechanisms to enable precision medicine.
Lin et al. (2026) studied this question.