Zanidatamab: reshaping the treatment landscape for HER2-positive gastroesophageal adenocarcinoma

Summary HER2 testing is essential in the pathological workup of metastatic gastroesophageal adenocarcinoma (GEA). Zanidatamab is a bispecific IgG1-like antibody that targets extracellular domains 2 and 4 of HER2 in a trans configuration. This biparotopic binding promotes receptor clustering, increases HER2 internalization, suppresses downstream signaling, and enhances immune-mediated cytotoxicity. The HERIZON-GEA-01 study was the first phase III trial to assess zanidatamab in metastatic GEA patients in combination with chemotherapy, with or without immunotherapy. While earlier studies with other anti-HER2 agents such as lapatinib and pertuzumab were negative, zanidatamab has emerged as an effective novel anti-HER2 therapy, demonstrating statistically significant and clinically relevant findings. It is highly likely that zanidatamab will become an important anti-HER2 component for HER2-positive gastrointestinal tumors, particularly for gastroesophageal adenocarcinoma.