HER2‐Targeted Antibody–Drug Conjugates–Associated Interstitial Lung Disease: A Pharmacovigilance Study Based on FDA Adverse Event Reporting System Data

Introduction Antibody–drug conjugates (ADCs) targeting the human epidermal growth factor receptor 2 (HER2), including trastuzumab deruxtecan (T‐DXd) and trastuzumab emtansine (T‐DM1), have already altered the treatment landscape for HER2‐positive malignancies. Interstitial lung disease (ILD) associated with ADCs presents as a fatal adverse reaction, yet it remains inadequately characterized in real‐world contexts. Aim This study was to refine the risk profiles of these agents using ILD cases drawn from the FDA Adverse Event Reporting System (FAERS) to examine the clinical features. Method ILD cases were extracted from FAERS. Disproportionality analyses and survival analyses were used to assess risk signals, onset kinetics, and mortality. Results T‐DXd exhibited stronger ILD signals and shorter time‐to‐onset than T‐DM1 (acute respiratory distress syndrome [73d vs. 403d, p = 0.033], pneumonitis [62.5d vs. 106d, p = 0.035]). No statistically significant differences were observed in fatal cases. Conclusion T‐DXd exhibits more reporting cases and an earlier onset time of ILD compared to T‐DM1. Proactive monitoring, including earlier radiographic screening, is warranted, particularly for patients at risk of acute respiratory distress syndrome and pneumonitis. Impact Statements This study provides crucial evidence through large‐scale real‐world data that T‐DXd is associated with a significantly higher number of reported cases of ILD and a shorter time to onset compared to T‐DM1. This comprehensive characterization of ILD signals and timing in real‐world clinical practice provides direct evidence for clinicians to conduct risk–benefit assessments and highlights the importance of early detection strategies starting within months of T‐DXd therapy.