Efficacy and safety of trastuzumab deruxtecan in HER2-high and HER2-low breast cancer: a systematic review and meta-analysis of randomized controlled trials

Breast cancer is the most common malignancy, with approximately ∼20% of cases involving HER2 overexpression. Trastuzumab deruxtecan (T-DXd), an HER2-targeted antibody–drug conjugate, is approved for HER2-high and HER2-low disease. This meta-analysis assessed four randomized controlled trials (DESTINY-Breast02, −03, −04, and −06; 2555 patients) from PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. A random-effects model revealed that T-DXd significantly improved progression-free survival (hazard ratio [HR] = 0.433; 95% confidence interval [CI]: 0.305–0.616; P &lt; 0.001; <i>I²</i> = 90.7%) and overall survival (HR = 0.720; 95% CI: 0.636–0.816; P &lt; 0.001; <i>I²</i> = 0%) versus control regimens, with consistent benefits across HER2 subgroups. However, T-DXd increased the risks of interstitial lung disease (relative risk [RR] = 13.832; P &lt; 0.001), decreased left ventricular ejection fraction (RR = 2.247; P &lt; 0.001), anemia, nausea, vomiting, decreased appetite, and alopecia; neutropenia and diarrhea risks were comparable between groups. These findings highlight T-DXd’s survival benefits and toxicity profile warranting monitoring.