Zolbetuximab: A First-in-Class Drug for Stomach Cancer

Zolbetuximab is an experimental monoclonal antibody that is currently being studied for use in the treatment of certain stomach (or gastric) cancers and pancreatic tumors.

Gastric cancers have been found to overexpress a protein called Claudin18.2. This protein is present predominantly in epithelial cells lining the gastric mucosa, where it is embedded in the cell membrane. Claudin18.2’s role in healthy tissues is to control the movement of molecules between the cells.

However, in cancerous tissues, due to the loss of cell-cell adhesion, Claudin18.2 proteins are exposed on the tumor cell surface where they are stably expressed in large amounts. Zolbetuximab is able to bind to Claudin18.2 on the cancer cell surface of gastric epithelial cells and trigger cell death (apoptosis) through two distinct immune system pathways.

Antibody-dependent cellular cytotoxicity

Also called antibody-dependent cell-mediated cytotoxicity (ADCC), ADCC is a defense mechanism used by your immune system to kill targeted cells. When zolbetuximab attaches to Claudin18.2 proteins on the cancer cell surface, it sends signals to recruit immune effector cells like natural killer cells. The effector cells then release cytotoxic substances that lyse and kill the gastric cancer cells.

Complement-dependent cytotoxicity

Complement-dependent cytotoxicity (CDC) is another immune mechanism used to induce cell death. When zolbetuximab binds to Claudin18.2 proteins on the tumor cell surface, it sends signals that recruit specific proteins called complements. Through a series of interactions between different complements and enzymes, a membrane attack complex (MAC) is formed. The MAC creates a hole in the membrane of gastric cancer cells, thereby inducing cell lysis and death.

As of now, there are two investigational studies centered on zolbetuximab: the SPOTLIGHT and GLOW clinical trials. Both are Phase 3 studies examining the safety and efficacy of this novel targeted therapy plus chemotherapy as a first-line treatment in people with locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are HER2-negative and Claudin18.2-positive.

Scientists are targeting this patient population because of the lack of treatment options. PD-L1 positive and HER2-positive gastric and gastroesophageal cancers can be treated using immunotherapy and trastuzumab, respectively. However, HER2-negative cancers fit neither category and targeted drug therapies are not typically used in their treatment. Standard chemotherapy regimens are currently the sole treatment option for this group of people and their average survival is limited to about 12 months. Fortunately, HER2-negative cancers tend to have elevated levels of Claudin18.2. This means that zolbetuximab would address a significant unmet need to extend survival in this patient population. Nonetheless, the use of zolbetuximab in combination with PD1/PD-L1 inhibitors has not been approved for use, as it is still undergoing testing in phase 3 clinical trials.

Topline findings from both SPOTLIGHT and GLOW trials show that zolbetuximab plus chemotherapy successfully improved progression-free survival for its target population. Based on these results, Astellas Pharma, the pharmaceutical company behind this novel drug, has submitted a Biologics License Application (BLA) for zolbetuximab. In July 2023, this BLA was granted priority review by the U.S. Food and Drug Administration (FDA). If approved, zolbetuximab would be the first Claudin18.2-targeted therapy available in America for patients living with advanced or metastatic gastric or GEJ adenocarcinoma whose tumors are HER2-negative and Claudin18.2-positive.