INTRODUCTION: HER2 mutations define a distinct, therapeutically actionable subset of NSCLC. Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.

METHODS: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.

RESULTS: Among 168 patients (median age 62 y; 59% female; 56% never-smokers), the ORR was 54.8% (95% confidence interval [CI]: 46.9-62.4) and disease control rate was 88.7% (95% CI: 82.9-93.1). Median PFS was 7.2 months (95% CI: 6.2-9.7) and median OS was 18.3 months (95% CI: 13.3-24.8). Treatment-naive patients (n = 18) achieved an ORR of 72.2% (95% CI: 46.5-90.3) and a median OS of 22.1 months (95% CI: 10.0-not evaluable). Patients with measurable brain metastases (n = 27) had an intracranial ORR of 74.1% (95% CI: 53.7-88.9), including 25.9% complete responses. Grade 3 or higher treatment-related adverse events occurred in 32% of patients. Interstitial lung disease/pneumonitis occurred in 14% (four fatal cases) of patients, without consistent predictors.

CONCLUSIONS: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naive patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with interstitial lung disease remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.