Abstract Rationale HER2-mutant non-small cell lung cancer (NSCLC) represents a rare and aggressive molecular subtype with limited targeted treatment options. Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, has demonstrated encouraging activity in early trials. However, pooled real-world estimates of efficacy and safety remain undefined. We performed a single-arm meta-analysis to evaluate clinical outcomes of T-DXd in HER2-mutant NSCLC. Methods A systematic search of PubMed, Scopus, and Cochrane databases identified studies evaluating T-DXd in HER2-mutant NSCLC. Extracted endpoints included overall response rate (ORR), disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and adverse events (AEs; grade ≥ 1, ≥ 3, and fatal). Pooled proportions were calculated using an inverse-variance random-effects model with Freeman-Tukey double-arcsine transformation. Sensitivity analyses were performed by dose level. Results Five studies (three single-arm and two randomized controlled trials) comprising 496 patients with HER2-mutant non-small cell lung cancer were included. The pooled overall response rate (ORR) was 48.0% (95% CI, 38.7-57.4; I² = 74.8%), and the disease control rate (DCR) was 87.9% (74.5-94.5; I² = 82.6%). Complete and partial responses were achieved in 2.1% and 45.7% of patients, respectively. The overall incidence of treatment-related adverse events (AEs) was 88% (62-100%; I² = 97%), with grade ≥ 3 AEs occurring in 32.1% (11.2-57.6%) and treatment-related deaths in 5% (0-18%). Conclusion Trastuzumab deruxtecan demonstrated meaningful clinical activity in HER2-mutant metastatic NSCLC, with nearly half of patients achieving an objective response and disease control in the vast majority. While treatment-related toxicities were common, most were mild to moderate, and severe or fatal events were relatively infrequent. These findings support T-DXd as an effective targeted therapy for this rare molecular subtype and highlight the need for continued research to refine dosing strategies and improve tolerability. This abstract is funded by: None
Vatvani et al. (2026) studied this question.