Fatigue Associated with Trastuzumab Deruxtecan in Solid Tumors: A Meta-Analysis and Pharmacovigilance Signal Detection Study

Introduction: With the increasing use of trastuzumab deruxtecan (T-DXd) in the treatment of solid tumors, fatigue has emerged as a clinically significant toxicity. We aimed to quantify the risk and incidence of T-DXd–associated fatigue using randomized evidence and single-arm data, and to corroborate these findings with the evidence from pharmacovigilance databases. Methods: We searched major databases and oncology meetings up to January 29th, 2025, for randomized controlled trials (RCTs) and single-arm studies in adults receiving T-DXd. Odds ratios, incidences, and 95% confidence intervals (CIs) were synthesized using Peto fixed- or random- effects models, according to the level of heterogeneity. Disproportionality was assessed using reporting odds ratios (RORs) from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). Additionally, time-to-onset data were analyzed using Weibull modeling. Results: Five RCTs (2,713 patients) and nine single-arm studies (1,096 patients) met the inclusion criteria. T-DXd increased fatigue risk (OR 1.51; 95% CI 1.28–1.78; I²=12%) as compared to the control. Pooled fatigue incidence in single-arm studies was 49% (95% CI 33%–65%; I²=94.9%). Fatigue was more frequent in breast cancer than in gastrointestinal tumors. Disproportionality signals were consistent (FAERS ROR 2.15, 95% CI 1.97–2.35; JADER ROR 3.33, 95% CI 1.38–8.03). The median onset was 33.5 days, with an early-failure pattern. Discussion: Fatigue associated with T-DXd is common, appears early, and is clinically significant. Heterogeneity and limitations of spontaneous reports (e.g., under-reporting and confounding) reduce the certainty of findings and underscore the need for standardized assessment and mitigation strategies. Conclusion: T-DXd is associated with substantially increased fatigue risk and high incidence across solid tumors. Early detection, proactive management, and routine monitoring of patientreported outcomes are recommended to support treatment adherence and quality of life.