[A New Molecular Targeted Agent for Gastric Cancer-The Anti-Claudin 18.2 Antibody, Zolbetuximab].

Abstract

The standard first-line treatment for unresectable advanced or recurrent gastric cancer(GC)and gastroesophageal junction cancer(GEJC)has been a platinum doublet chemotherapy. Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy. However, many patients do not derive benefit from anti-HER2 targeted therapies or ICIs, and new therapeutic targets have been explored. CLDN18.2 has emerged as a tissue-specific therapeutic target in gastric cancer. Zolbetuximab, a first-in-class chimeric IgG1 monoclonal antibody targeting CLDN18.2, has been developed. Zolbetuximab induces cancer cell death through antibody-dependent cellular cytotoxicity(ADCC)and complement-dependent cytotoxicity(CDC). Recently, zolbetuximab with chemotherapy improved survival rates in HER2-negative CLDN18.2-positive previously untreated patients with unresectable advanced or recurrent GC/GEJC, leading to its approval in Japan and its establishment as a standard treatment. GC/GEJC with early onset, scirrhous type or peritoneum dissemination commonly express CLDN18.2. The emergence of this novel therapeutic option is of great significance in clinical practice. We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.