Mapping the antibody–drug conjugate safety landscape: a real-world pharmacovigilance study of platform-driven and target-modulated toxicity

Purpose To characterize and compare the real-world safety profile of antibody–drug conjugates (ADCs) using large-scale pharmacovigilance data and to identify factors associated with fatal reporting. Methods We conducted a retrospective pharmacovigilance study using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from Q1 2004 to Q1 2025. A total of 38,371 reports associated with 13 approved ADCs were included. Safety profiles were evaluated across system organ classes, technological platforms, and target distributions. Multivariable logistic regression was further used to evaluate drug-, platform-, SOC-, and patient/report-level factors associated with fatal reporting. Results Across all ADCs, blood and lymphatic disorders, general disorders and administration-site conditions, investigations, and respiratory, thoracic mediastinal disorders constituted a consistent core toxicity pattern, although marked organ-specific heterogeneity was observed across individual ADCs and linker-payload Platforms. The vedotin platform was associated with bone marrow suppression and neurotoxicity, with marked inter-drug variability (e.g., brentuximab vedotin showed severe infections and acute organ injury with high mortality; enfortumab vedotin predominantly manifested severe dermatologic toxicity; and tisotumab vedotin showed prominent ocular toxicity). The calicheamicin platform was characterized by high-mortality hepatotoxicity and bone marrow suppression (gemtuzumab ozogamicin: fatal gastrointestinal complications and infections; inotuzumab ozogamicin (INO): progressive liver injury and systemic inflammatory responses). The DxD platform exhibited gastrointestinal, pulmonary, and hepatic toxicities with differing risk concentrations: trastuzumab deruxtecan was primarily associated with interstitial lung disease (ROR = 57.1). Notably, ADCs targeting the same antigen on different platforms (HER2, Trop-2) showed marked toxicity divergence. In multivariable analyses, INO showed the strongest drug-level association with fatal reporting (adjusted OR = 2.61, 95% CI 2.27–2.99), while the calicheamicin platform showed the strongest platform-level association relative to vedotin (adjusted OR = 1.75, 95% CI 1.58–1.94). Age ≥75 years, male sex, and a greater number of co-reported preferred terms were also associated with increased odds of fatal reporting. Conclusion ADC safety profiles showed both shared and distinct patterns across linker–payload platforms and therapeutic targets, while fatal-reporting associations also varied according to individual ADCs and patient/report-level characteristics. These findings support a multidimensional approach to ADC risk assessment and may inform more tailored safety monitoring and risk-based clinical decision-making.