COMPREHENSIVE SAFETY EVALUATION OF TRASTUZUMAB DERUXTECAN IN HER2-POSITIVE METASTATIC BREAST CANCER: A META-ANALYSIS AND DISPROPORTIONALITY ANALYSIS
Author(s)
Sweta Sawan, MPharm1, RATHOD MAHESH, PhD Scholar1, Mahesh Prabhakarrao Jagtap, MPharm2, Rohit Kachhadiya, MPharm2, Krishna Undela, PhD1.
1National Institute of Pharmaceutical Education and Research, Guwahati, Assam, India, 2Innomagine Consulting Private Limited, Hyderabad, India.
1National Institute of Pharmaceutical Education and Research, Guwahati, Assam, India, 2Innomagine Consulting Private Limited, Hyderabad, India.
OBJECTIVES: Trastuzumab Deruxtecan (T-DXd) is the current standard of care for second-line HER2-positive metastatic breast cancer (mBC). However, its full safety profile remains incompletely characterized. This study comprehensively characterized the safety profile of T-DXd in HER2-positive mBC and identified real-world safety signals beyond those captured in randomized controlled clinical trials (RCTs).
METHODS: We searched PubMed and Embase in November 2025 for interventional studies. Heterogeneity was assessed using I-squared and Chi-square statistics, and fixed- or random-effects models were applied accordingly. Risk ratios (RRs) and pooled incidence proportions with 95% confidence intervals (CIs) were calculated for comparative and single-arm studies, respectively. Pharmacovigilance (PV) analysis using the FDA Adverse Event Reporting System (FAERS) from 2019 to 2025 was performed using the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM). Signal refinement was performed to control for confounding from concomitant medications.
RESULTS: Two Phase III RCTs (661 patients) and three single-arm studies (314 patients) were included. Common any-grade adverse events (AEs) included interstitial lung disease (ILD), neutropenia, vomiting, and alopecia. Grade ≥3 toxicities were fatigue (RR 7.06; 95% CI 2.11-23.54), neutropenia (RR 5.22; 95% CI 2.89-9.41), vomiting (RR 3.74; 95% CI 1.10-12.65), and anemia (RR 1.89; 95% CI 1.07-3.33). Pooled incidence was highest for neutropenia (17%) and anemia (12%). PV analysis identified 55 safety signals, with ILD showing the strongest signal. Potential novel signals included pseudocirrhosis, ascites, pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, keratitis, eye hematoma, and limbal stem cell deficiency. Overall risk of bias was low in RCTs (RoB 2) and serious in single-arm studies (ROBINS-I)
CONCLUSIONS: Grade ≥3 neutropenia was the most frequent severe AE, and PV analysis identified potential novel safety signals beyond clinical trial findings. These findings highlight the need for enhanced monitoring strategies and further prospective studies to validate these emerging safety concerns.
METHODS: We searched PubMed and Embase in November 2025 for interventional studies. Heterogeneity was assessed using I-squared and Chi-square statistics, and fixed- or random-effects models were applied accordingly. Risk ratios (RRs) and pooled incidence proportions with 95% confidence intervals (CIs) were calculated for comparative and single-arm studies, respectively. Pharmacovigilance (PV) analysis using the FDA Adverse Event Reporting System (FAERS) from 2019 to 2025 was performed using the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM). Signal refinement was performed to control for confounding from concomitant medications.
RESULTS: Two Phase III RCTs (661 patients) and three single-arm studies (314 patients) were included. Common any-grade adverse events (AEs) included interstitial lung disease (ILD), neutropenia, vomiting, and alopecia. Grade ≥3 toxicities were fatigue (RR 7.06; 95% CI 2.11-23.54), neutropenia (RR 5.22; 95% CI 2.89-9.41), vomiting (RR 3.74; 95% CI 1.10-12.65), and anemia (RR 1.89; 95% CI 1.07-3.33). Pooled incidence was highest for neutropenia (17%) and anemia (12%). PV analysis identified 55 safety signals, with ILD showing the strongest signal. Potential novel signals included pseudocirrhosis, ascites, pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, keratitis, eye hematoma, and limbal stem cell deficiency. Overall risk of bias was low in RCTs (RoB 2) and serious in single-arm studies (ROBINS-I)
CONCLUSIONS: Grade ≥3 neutropenia was the most frequent severe AE, and PV analysis identified potential novel safety signals beyond clinical trial findings. These findings highlight the need for enhanced monitoring strategies and further prospective studies to validate these emerging safety concerns.
Conference/Value in Health Info
2026-09, ISPOR Asia Pacific 2026, Bangkok, Thailand
Value in Health, Volume 55, Issue S1
Code
CO9
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, SDC: Oncology, STA: Biologics & Biosimilars