Zolbetuximab: An Investigational First-Line Treatment for CLDN18.2-positive, HER2-negative Gastric and Gastro-oesophageal Junction Cancer

Biomarker-based targeted therapies have changed the cancer treatment paradigm. While early-stage gastric and gastro-oesophageal junction (GOJ) adenocarcinomas can benefit from surgery, advanced presentations of these diseases have limited therapeutic options and poor prognoses. Zolbetuximab, a chimeric monoclonal antibody targeting Claudin 18.2 (CLDN18.2), exerts its effect through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. It has emerged as a promising treatment for advanced gastric/GOJ cancer. Clinical trials have assessed its efficacy and safety across multiple phases, demonstrating significant improvements in progression-free survival and overall survival. The safety profile of zolbetuximab primarily includes manageable gastrointestinal adverse events, namely nausea and vomiting. Zolbetuximab's potential extends beyond its primary indication, with on-going trials exploring its efficacy in other CLDN18.2-expressing malignancies, such as pancreatic adenocarcinoma. This review highlights zolbetuximab's potential as a first-line therapy for CLDN18.2-positive, HER2-negative gastric and GOJ adenocarcinomas, shedding light on its mechanism of action, clinical trial results, safety profile and current treatment landscape.