Multicenter prospective EN-MARK study: efficacy of third-line trastuzumab deruxtecan and dynamic changes in biomarkers, including HER2 status

<h3>Background</h3> Human epidermal growth factor receptor 2 (HER2) is overexpressed in ∼20% of advanced gastroesophageal adenocarcinomas (GEAs). Trastuzumab (T-mab) is the standard first-line treatment for HER2-positive GEA, and trastuzumab deruxtecan (T-DXd) has demonstrated clinical efficacy in later-line settings. However, the potential loss of HER2 expression following T-mab treatment raises concerns about the subsequent effectiveness of T-DXd. The temporal dynamics of HER2 expression across treatment lines are not well understood. <h3>Design</h3> We designed a prospective, single-arm, multicenter study to investigate the association between the efficacy of third-line T-DXd and changes in HER2 status in tumor tissue and blood after first-line T-mab treatment in patients with HER2-positive GEA. The aim is to inform the optimal clinical use of T-DXd. Serial tumor and/or blood re-biopsies will be carried out at each line of treatment following first-line therapy. The study consists of two parts. In part 1, we will evaluate biomarker dynamics—specifically HER2 status and circulating tumor DNA alterations—during second-line therapy. In part 2, we will assess the efficacy and safety of third-line T-DXd in relation to these biomarker changes. Approximately 120 patients will be enrolled in part 1 and 50 in part 2.