HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

Abstract

Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.

Keywords: Antibody–drug conjugates; Bispecific antibody; Gastric cancer; Gastric/gastroesophageal junction adenocarcinoma; HER2-targeted therapy; Immunotherapy; Monoclonal antibody; Tyrosine kinase inhibitor.

Fig. 1

Mechanism of action and potential resistance mechanisms of HER2-targeted therapy: A HER2-targeted ADCs enter cells through endocytosis and release toxins that act on microtubules, DNA, or other materials, thereby inhibiting cell growth, proliferation, survival and metastasis. B HER2-targeted antibodies inhibit downstream signaling by binding to the extracellular domain of HER2 and preventing the formation of dimers between HER2 and other EGFR family members, in addition to releasing perforins and granzymes to act on target cells through ADCC. C TKIs inhibit signal transduction by binding to the intracellular tyrosine kinase domain of HER2. D HER2 heterogeneity, loss of HER2-positivity, mutation/amplification, alterations in intracellular signaling, protein overexpression, miRNAs, and abnormalities in either component of the ADC process can all lead to the development of drug resistance, which prevents cell death