Development of HER2-targeted therapies for gastrointestinal cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) amplification is an important molecular mechanism underlying carcinogenesis and is associated with various types of cancer. Although the advancement of HER2-targeted therapy has been the most pronounced in breast cancer, interest has emerged in exploring the efficacy of HER2-targeted therapies in gastrointestinal (GI) cancers. In particular, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric or oesophagogastric junction cancer. Although subsequent trials involving lapatinib, ado-trastuzumab emtansine (T-DM1), and pertuzumab have failed to show significant survival benefits for HER2-positive gastric or oesophagogastric junction cancer, several trials are currently ongoing. HER2-targeted therapy has also been tested in patients with other GI cancers. Some combination therapies, such as trastuzumab plus pertuzumab, have shown promising results in single-arm phase II studies. Moreover, trials of novel anti-HER2 agents, including trastuzumab deruxtecan (T-DXd), tucatinib and margetuximab – which demonstrated improvement of clinical outcomes in breast cancer – are ongoing for GI cancers. In this review, we provide an overview of the current status of HER2-targeted therapies and focus on future perspectives for overcoming issues in the treatment of HER2-positive GI cancer.