Mucosal, Ocular, and Pulmonary Adverse Events Reported with Datopotamab Deruxtecan: An Indication-Restricted Disproportionality Analysis of the FDA Adverse Event Reporting System

Background/Objectives: Datopotamab deruxtecan was approved in 2025 for hormone receptor-positive, HER2-negative metastatic breast cancer and for EGFR-mutated non-small cell lung cancer (NSCLC); its safety profile in routine use has not been described. We characterized adverse event reporting for the agent and asked whether the events reported most disproportionately are those that carry the reported harm. Methods: Reports naming datopotamab deruxtecan as a primary suspect in the FDA Adverse Event Reporting System (FAERS, 2025Q1–2026Q1) were stratified by recorded indication and compared with all other reports recording the same indication. A signal required at least three reports and pre-specified frequentist (reporting odds ratio (ROR), proportional reporting ratio, chi-square), Bayesian (lower credibility bound of the information component, IC025), and multiplicity-adjusted thresholds. Sacituzumab govitecan served as a within-class comparator, reference pools were pruned of agents causing the same event, and outcomes were recalculated after excluding reports coding disease progression. Results: Among 416 reports (196 breast, 118 NSCLC), mucosal and ocular events dominated: the ROR for stomatitis was 21.50 (95% CI: 15.04–30.74) and 17.72 (9.93–31.63), with keratitis, oral candidiasis, and dry eye also qualifying. Against sacituzumab govitecan, stomatitis persisted (19.75), while myelosuppressive and gastrointestinal terms were markedly less reported. Interstitial lung disease met the Evans criteria but not the Bayesian or multiplicity threshold in the breast stratum (2.51), and did not meet any criterion in the lung stratum (2.09) or against the comparator; the reports carrying it nevertheless recorded the heaviest harm, with eighteen out of nineteen being serious (94.7%, 95% CI: 74.0–99.9) and five out of nineteen being fatal (26.3%, 95% CI: 9.1–51.2), while no fatal outcome remained among the 66 progression-free mucosal reports. Trastuzumab deruxtecan supplied 30.3% of pulmonary reports in the breast reference pool; removing it raised the estimate to 3.70 with an IC025 of 0.41. Conclusions: Reporting for datopotamab deruxtecan is dominated by mucosal and ocular toxicity, whereas interstitial lung disease is reported less often but in reports recording a far higher proportion of serious and fatal outcomes. Its absence from the primary signal lists reflects a comparison base containing agents that cause the same event rather than an absence of risk, and monitoring intensity should not follow the magnitude of disproportionality. Spontaneous reports are subject to under-reporting, stimulated reporting, and incomplete data, and disproportionality describes patterns of reporting rather than incidence or risk.