Zanidatamab in the treatment of esophagogastric adenocarcinoma

Esophagogastric cancer (EGC) remains a leading cause of cancer‑related mortality worldwide. Approximately 15-20% of advanced EGC overexpress human epidermal growth factor receptor 2 (HER2). Since 2010, trastuzumab in combination with platinum and fluoropyrimidine chemotherapy has been the cornerstone of first-line therapy for HER2-positive advanced EGC, with a modest overall survival benefit. The addition of pembrolizumab to trastuzumab and chemotherapy in the KEYNOTE-811 trial has improved outcomes in PD-L1‑positive tumors. Despite these advances, median overall survival remains below 20 months. Zanidatamab is a novel biparatopic HER2-directed antibody, designed to bind to two distinct extracellular domains of HER2, promoting receptor clustering, enhanced internalization, and immune-mediated cytotoxicity. This Drug Evaluation reviews the pharmacology, pharmacokinetics, clinical development, efficacy, safety, and regulatory status of zanidatamab in HER2-positive EGC. The phase III HERIZON-GEA-01 trial evaluated zanidatamab (with or without tislelizumab) plus chemotherapy as first-line treatment for HER2-positive advanced EGC. This trial demonstrated clinically meaningful improvements in progression-free and overall survival versus trastuzumab-based therapy, leading to FDA approval of zanidatamab plus chemotherapy, with or without tislelizumab, as first‑line treatment for HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma. Key questions remain regarding optimal patient selection, the role of tislelizumab across PD-L1 subgroups, sequencing with antibody-drug conjugates, and long-term safety.