Multisystem toxicity signals of antibody–drug conjugates in solid tumors: A FAERS pharmacovigilance analysis, 2020–2025.

Abstract

376 Background: Antibody-drug conjugates (ADCs) have transformed treatment of solid tumors; however, payload-driven toxicities may affect symptom burden, treatment continuity, and outcomes. Clinical trials are often underpowered to detect delayed or multisystem adverse events and may not reflect real-world populations. Methods: We conducted a retrospective observational pharmacovigilance study using case-level disproportionality analysis of spontaneous reports in the U.S. FDA Adverse Event Reporting System (FAERS, 2020–2025). Reports involving trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) were identified and deduplicated. Prespecified pulmonary, hematologic (heme), and gastrointestinal (GI) toxicity composites were evaluated using reporting odds ratios (RORs) with 95% confidence intervals. Reporting latency was assessed using therapy start and initial FDA receipt dates. Results: Among 8,462,073 FAERS reports, 16,932 involved an ADC. T-DXd had the strongest pulmonary safety signal, particularly for interstitial lung disease (ILD) (ROR, 50.3) and pneumonitis (ROR, 32.3), with a pulmonary composite ROR of 35.0. SG had the strongest heme signal (composite ROR, 10.1), driven mainly by neutropenia (ROR, 15.0) and febrile neutropenia (ROR, 13.7). More modest hematologic signals were observed with T-DM1 (ROR, 3.8) and T-DXd (ROR, 3.4). GI adverse events, including nausea, diarrhea, and vomiting, were disproportionately reported with T-DXd (composite ROR, 2.8) and SG (ROR, 2.6). Median reporting latency ranged from 70 days for Dato-DXd to 232 days for T-DM1. Conclusions: In this contemporary cross-ADC FAERS analysis, pulmonary signals were most prominent with T-DXd, hematologic signals with SG, and gastrointestinal signals with both. Direct comparison across four ADCs provides a comparative view of agent-specific multisystem toxicity beyond single-agent trial data. Key findings. Outcome Dato-DXd (n=199) SG (n=4,680) T-DM1 (n=2,617) T-DXd (n=9,436) Serious adverse event 1.2 (0.9–1.6) 7.9 (7.1–8.7) 2.6 (2.3–2.8) 2.2 (2.1–2.3) Death 4.7 (3.4–6.3) 3.3 (3.1–3.5) 1.9 (1.7–2.1) 3.5 (3.3–3.6) Pulmonary composite 10.0 (5.1–19.6) 4.4 (3.5–5.3) 5.5 (4.29–7.0) 35.0 (33.0–37.2) ILD 15.5 (7.3–33.0) 2.6 (1.8–3.7) 4.8 (3.3–6.9) 50.3 (47.0–53.9) Pneumonitis 6.9 (1.7–28.0) 10.0 (7.8–12.7) 9.8 (7.1–13.6) 32.3 (29.3–35.8) Heme composite 1.0 (0.4–2.6) 10.1 (9.4–10.9) 3.8 (3.3–4.4) 3.4 (3.1–3.6) Neutropenia 0.3 (0.0–5.1) 15.0 (13.7–16.5) 1.7 (1.2–2.4) 3.1 (2.8–3.3) Febrile neutropenia 1.4 (0.2–10.2) 13.7 (12.0–15.7) 1.4 (0.8–2.4) 2.6 (2.3–2.9) GI composite 1.0 (0.6–1.8) 2.6 (2.4–2.8) 1.1 (1.0–1.3) 2.8 (2.6–2.9) Median reporting latency, days (IQR) 70 (105) 111 (213) 232 (387) 144 (263) Values are reporting odds ratios with 95% confidence intervals unless otherwise specified.