Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer

Abstract

Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.

Keywords: Antibody–drug conjugate; Gastric cancer; HER-2; Review; Topoisomerase I inhibitor.

Fig. 1

Antibody–drug conjugate functional mechanism and bystander antitumor effect of trastuzumab deruxtecan. T-DXd trastuzumab deruxtecan; HER2 human epidermal growth factor receptor 2

Fig. 2

Management flowchart of T-DXd-induced interstitial lung disease. BNP brain natriuretic peptide; CMV cytomegalovirus; CRP c-reactive protein; CT computed tomography; DL_CO diffusing capacity of the lung carbon monoxide; HRCT high resolution computed tomography; ILD interstitial lung disease, KL-6 Krebs von den Lungen-6; LDH lactate dehydrogenase; SP-D pulmonary surfactant protein-D; T-DXd trastuzumab deruxtecan