Zolbetuximab for Unresectable and Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma: A Review of Literature

This article comprehensively reviews the working, efficacy, and safety profile of zolbetuximab. Zolbetuximab is a pioneering chimeric monoclonal antibody designed to target Claudin 18.2 (CLDN18.2), a tight junction protein frequently overexpressed in various gastrointestinal cancers, including gastric (G) and gastroesophageal junction (GEJ) adenocarcinomas. This drug has captured attention in the treatment of unresectable and metastatic G/GEJ cancer, especially in HER2-negative patients whose tumours express CLDN18.2. Zolbetuximab is a drug that binds to CLDN18.2, and its binding initiates an immune response that attacks and kills the cancer cells. It is typically co-prescribed with fluoropyrimidine and platinum-containing chemotherapy. The drug (formerly IMAB362), brand name Vyloy, was developed by Astellas Pharma, Tokyo, Japan. After multiple rounds of clinical trials, it was approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for locally advanced, unresectable cancer, establishing itself as a promising option for advanced G/GEJ cancers. Studies reveal that it targets CLDN18.2 for the selective killing of cancer cells while sparing most healthy tissues. Zolbetuximab has demonstrated a significant improvement in progression-free survival (PFS) when combined with chemotherapy (like mFOLFOX6 or CAPOX). Also, it showed prolonged PFS compared to chemotherapy alone in previously untreated, CLDN18.2-positive, HER2-negative patients. Zolbetuximab has also shown improvements in overall survival (OS), regardless of whether the cancer progresses. This is a crucial benefit for patients with advanced G/GEJ adenocarcinomas. Additionally, zolbetuximab's dual action triggers antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). This enhances the immune system's ability to destroy cancerous cells and results in highly potent tumour destruction compared with chemotherapy alone. Zolbetuximab is a relatively safe drug with a few adverse effects. The most frequently reported side effects were gastrointestinal, namely nausea, fatigue, vomiting, decreased appetite, diarrhea, neutropenia, anemia, and thrombocytopenia, potentially due to specific CLDN18.2 expression in the gastric mucosa. Its side effects are generally manageable, with no unexpected toxicity beyond those typically seen in patients receiving chemotherapy.