Redefining First-Line HER2-Positive Advanced Gastric Cancer: From Trastuzumab-Based Chemoimmunotherapy to Zanidatamab and Next-Generation HER2 Targeting.

backgroundFor more than a decade after the ToGA trial, trastuzumab plus platinum-fluoropyrimidine chemotherapy remained the only established first-line HER2-targeted standard for unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. The treatment landscape is now changing rapidly through pembrolizumab-based chemoimmunotherapy, zanidatamab-based therapy, and antibody-drug conjugate strategies.

methodsThis narrative review summarizes pivotal and emerging evidence for first-line HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma. PubMed/MEDLINE was searched through June 2026 using combinations of the terms HER2, gastric cancer, gastroesophageal junction, first-line treatment, trastuzumab, pembrolizumab, zanidatamab, tislelizumab, and trastuzumab deruxtecan. Priority was given to phase III trials, peer-reviewed reports, major conference updates, and guideline documents relevant to clinical practice.

resultsToGA established trastuzumab plus chemotherapy as a first-line standard, but subsequent attempts to improve outcomes by adding or substituting HER2-directed agents, including lapatinib, high-dose trastuzumab, pertuzumab, and trastuzumab emtansine, did not displace trastuzumab-based therapy. KEYNOTE-811 demonstrated that pembrolizumab added to trastuzumab and chemotherapy improves response, progression-free survival, and overall survival, particularly in PD-L1-positive disease. The phase III HERIZON-GEA-01 trial has now shown that zanidatamab plus chemotherapy, with or without tislelizumab, improves progression-free survival compared with trastuzumab plus chemotherapy, and that zanidatamab plus tislelizumab and chemotherapy improves overall survival. Trastuzumab deruxtecan is also moving from later-line therapy into first-line development through platinum-free combinations with fluoropyrimidine and immune checkpoint blockade.

conclusionsFirst-line treatment of HER2-positive advanced gastric cancer is entering a second transformation. The central clinical question is shifting from whether HER2 blockade should be combined with chemotherapy to which HER2-targeted platform should anchor first-line therapy, how immune checkpoint inhibition should be integrated, and how HER2 heterogeneity and biomarker evolution should guide treatment sequencing.