HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

SIMPLE SUMMARY: The human epidermal growth factor receptor 2 (HER2) became the first routinely targeted biomarker in the management of stomach cancers when the monoclonal antibody trastuzumab given with chemotherapy was shown to improve patient survival in 2010. Over the past decade, we have developed our understanding of how HER2-directed drugs lose their effectiveness and have now reached a phase where several new drugs are being developed simultaneously for HER2-positive stomach cancers. In this paper, we will summarise the evidence supporting HER2 targeting in stomach cancers, review mechanisms of drug resistance and outline the new treatment approaches that may change the way we treat this disease. ABSTRACT: Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of HER2 gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. Although limited progress was made in the decade following ToGA, there is now an abundance of novel therapeutic approaches undergoing investigation in parallel. Additionally, new data from randomised trials have indicated efficacy of the antibody-drug conjugate trastuzumab deruxtecan in chemorefractory patients and increased responses with the addition of first-line immune checkpoint blockade to trastuzumab and chemotherapy. This review will outline the data supporting HER2 targeting in gastric cancers, discuss mechanisms of response and resistance to HER2-directed therapies and summarise the emerging therapies under clinical evaluation that may evolve the way we manage this subset of gastric cancers in the future.