Combining zanidatamab, FOLFOX, and pembrolizumab as first-line therapy for HER2/PD-L1–positive gastroesophageal adenocarcinoma: The phase ll IKF-090/AIO ZANGEA trial with translational analysis.

Abstract

TPS4244 Background: Gastroesophageal adenocarcinoma (GEA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating previously untreated, metastatic HER2/PD-L1 positive GEA involves a combination of doublet chemotherapy, which consists of a platinum compound and a fluoropyrimidine, in combination with trastuzumab and pembrolizumab. Recently, the phase 3 HERIZON-GEA-01 trial has shown improved survival for zanidatamab in combination with CAPOX or fluoropyrimidine and cisplatin with the PD-1 inhibitor tislelizumab compared to chemotherapy and trastuzumab. Zanidatamab is a bispecific antibody that targets two distinct HER2 epitopes (domains 2 and 4), thereby crosslinking neighboring HER2 receptors and inducing receptor clustering. This leads to enhanced HER2 internalization, reduced downstream signaling, and increased Fc-mediated immune effector functions, compared with trastuzumab. There is currently insufficient evidence regarding the combination of zanidatamab with the frequently used chemotherapy backbone FOLFOX and no available data on combining this regimen with the PD-1 inhibitor pembrolizumab. Furthermore, biomarkers to predict response and toxicities are lacking. Methods: The ZANGEA study is an open-label, single-arm, multicenter, translational phase II trial designed to assess the efficacy, safety, tolerability and translational aspects of zanidatamab in combination with FOLFOX and pembrolizumab in patients with 1 st line HER2/PD-L1-positive GEA. The primary endpoint is the progression-free survival rate after 12 months. Secondary objectives include safety and tolerability, efficacy in terms of objective response rate, progression-free and overall survival and translational markers, such as blood-based signatures (e.g. inflammatory cytokines), microbiota signatures, dietary patterns or microbiota derived metabolites that may correlate with therapy response or side-effects. In total, 80 patients will be recruited to show an PFS at 12 months of 55% compared to 46% with trastuzumab/pembrolizumab/chemotherapy (KeyNote 811). Enrollment started on 16 Jan 2026. Clinical trial information: NCT07176312 .