Comparative serious safety reporting signals for antibody-drug conjugates versus HER2-targeted non-ADC therapies: A FAERS analysis (2020–2025).

Abstract

e13084 Background: Antibody–drug conjugates (ADCs) have transformed systemic cancer therapy but are associated with distinct and potentially severe toxicities. Post-marketing pharmacovigilance databases such as the FDA Adverse Event Reporting System (FAERS) enable detection of rare or serious adverse event (AE) reporting signals but do not permit incidence estimation or causal attribution. Comparative real-world safety data across ADCs remains limited. Methods: We performed a retrospective pharmacovigilance analysis of serious FAERS reports (2020–2025), comparing sacituzumab govitecan, trastuzumab deruxtecan, trastuzumab emtansine, and datopotamab deruxtecan with HER2-targeted non-ADC therapies analyzed as a composite reference. Analyses focused on prespecified pulmonary, cardiac, and gastrointestinal toxicities; other toxicities were not comprehensively evaluated. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals. Death was analyzed as a reported outcome with age stratification; FAERS does not permit attribution to drug exposure or disease progression. Results: Among serious reports, T-DXd showed the strongest pulmonary safety signals, including interstitial lung disease (ROR 12.86, 95% CI 11.20–14.76) and pneumonitis (ROR 8.16, 95% CI 6.83–9.76). T-DM1 demonstrated moderate pulmonary signals and a cardiac signal for left ventricular dysfunction (ROR 1.92, 95% CI 1.43–2.57). SG was characterized by prominent gastrointestinal toxicity, with diarrhea as the most frequently reported serious GI event (ROR 1.01), while pneumonitis showed elevated disproportionality despite lower frequency (ROR 2.34). Death was disproportionately reported across ADCs versus HER2-targeted non-ADC therapies, with elevated signals for Dato-DXd (ROR 4.78), T-DXd (ROR 2.97), SG (ROR 2.24), and T-DM1 (ROR 1.28). Age-stratified analyses showed comparable or higher death disproportionality among patients < 40 years versus ≥40 years. Conclusions: ADCs exhibit distinct serious safety reporting profiles compared with HER2-targeted non-ADC therapies, with prominent pulmonary signals for T-DXd and GI toxicity for SG. Reported death disproportionality likely reflects the severity and treatment-refractory nature of the populations rather than drug-attributable mortality and should be interpreted cautiously, given the limitations of FAERS. This focused, hypothesis-generating analysis underscores the importance of vigilant toxicity monitoring and highlights the need for complementary real-world and prospective studies incorporating clinical context, broader toxicity characterization, and causal attribution.