Comparative safety profiles of antibody-drug conjugates: a real-world analysis of monotherapy and combination regimens in solid tumors.

The expanding clinical use of Antibody-Drug Conjugates (ADCs) necessitates a clearer understanding of their real-world toxicity profiles across diverse clinical settings. This retrospective pharmacovigilance study analyzed 19,697 adverse event (AE) reports for seven approved ADCs from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2025). Using disproportionality analysis validated by multivariable logistic regression, we identified safety signals for both monotherapy and combination regimens. The analysis revealed that toxicity profiles are strongly driven by an ADC's molecular structure and treatment setting. Target-specific 'on-target, off-tumor' effects were prominent, linking Nectin cell adhesion molecule 4 (NECTIN-4) targeting to skin reactions, Trophoblast cell-surface antigen 2 (TROP2) to gastrointestinal toxicities, and both folate receptor α (FRα) and tissue factor (TF) to ocular disorders. Furthermore, payload and linker types drove distinct toxicities; topoisomerase I inhibitors were associated with increased respiratory toxicity and mortality, while non-cleavable linkers conferred a significantly stronger risk of hepatobiliary toxicity. Combination regimens not only amplified specific risks, such as endocrine disorders with immune checkpoint inhibitors (ICIs), but also fundamentally reshaped toxicity kinetics, accelerating AE onset with ICIs while significantly delaying it with other combinations. This real-world analysis confirms that ADC toxicities are highly specific to their molecular design and clinical context, highlighting that understanding these complex structural and kinetic interplays is essential for optimizing safety management in clinical practice.