Multinational, retrospective study of real-world outcomes with trastuzumab deruxtecan for HER2-mutant non-small cell lung cancer

HER2 mutations define a therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated activity in clinical trials, but real-world data are limited. The TRACER/HERTras real-world cohort evaluated T-DXd for advanced HER2-mutant NSCLC in patients across 68 centers in Europe and Israel. Between August 2021 and January 2025, 168 patients (median age 62 years; 59% female; 56% never-smokers) received T-DXd outside clinical trials. The objective response rate (ORR) was 54.8% (95% CI 46.9-62.4) and the disease control rate was 88.7% (82.9-93.1); median progression-free survival (PFS) was 7.2 months (6.2-9.7) and median overall survival (OS) was 18.3 months (13.3-24.8). Among 18 treatment-naïve patients, the ORR was 72.2% (95% CI 46.5-90.3) and the median OS was 22.1 months (10.0-NE). Among 27 patients with measurable brain metastases, the intracranial ORR was 74.1% (95% CI 53.7-88.9) including 25.9% complete responses. Grade ≥ 3 treatment-related adverse events occurred in 32% of patients, with interstitial lung disease/pneumonitis in 14% (four fatal cases), without consistent predictors. The authors conclude that in this largest real-worl cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases, who were largely excluded from prior studies.