Abstract
BACKGROUND: Despite advances in the multimodal treatment of resectable esophagogastric adenocarcinoma (EGA), relapse rates remain high, resulting in a cure rate of <50%. Recently, perioperative durvalumab in combination with chemotherapy (ctx) has shown improved event-free survival in biomarker-unselected patients with resectable EGA. However, human epidermal growth factor receptor 2 (HER2)-targeted therapy has not yet been established as a treatment for this disease in the perioperative setting. While the combination of HER2-targeting antibodies and neoadjuvant ctx leads to an increased histopathological response rate, a survival benefit has not yet been demonstrated. Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate, has demonstrated superior efficacy in second- and third-line treatment of metastatic HER2-positive EGA compared with chemotherapies, as well as high response rates when combined with ctx in the first-line setting. AIM: This study aims to evaluate the feasibility, safety, and activity of various neoadjuvant T-DXd-based combination regimens in patients with HER2-positive, locally advanced, resectable EGA. The primary endpoint is the feasibility rate across the different cohorts. TRIAL DESIGN: UCCL-IKF-NeoART is an international, open-label, non-randomized phase Ib/II platform trial evaluating T-DXd in sequential cohorts, each combining the drug with a different ctx regimen. Every cohort includes an initial safety run-in phase.