The phase III HERIZON-GEA-01 study showed that the combination of the bispecific antibody zanidatamab (Ziihera) with chemotherapy, with or without the PD-1 inhibitor tislelizumab, outperformed trastuzumab plus chemotherapy in the first-line treatment of patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma.[2][3] The study randomized 914 patients from approximately 300 centers in more than 30 countries, with HER2 defined as IHC 3+ or IHC 2+ with ISH positive.[2][3][4] Patients had unresectable locally advanced, recurrent, or metastatic HER2+ GEA, including adenocarcinomas of the stomach, gastroesophageal junction, and esophagus.[2][3][4] The primary endpoints were progression-free progression (PFS) by independent central review and overall survival (OS).[2][3][4] The combination of zanidatamab with tislelizumab and chemotherapy achieved a statistically significant and clinically meaningful benefit in OS, with a median benefit of more than two years.[2][10] Benefits in OS and PFS were consistent across major subgroups, including region and PD-L1 status.[2] Gastroesophageal adenocarcinoma is the fifth most common cancer type worldwide, approximately 20% of patients have HER2+ disease, and the five-year survival rate is less than 30% for gastric cancer and around 19% for GEA.[2][3]