The U.S. Food and Drug Administration (FDA) has granted approval to zolbetuximab-clzb (Vyloy), in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin 18.2-positive and HER2-negative. This approval marks a significant advancement in the treatment landscape for these cancers, addressing a critical unmet need.
Mechanism of Action and Clinical Significance
Zolbetuximab-clzb is a first-in-class antibody that targets claudin 18.2, a protein expressed at cell junctions in the gastrointestinal tract. In cancerous tissues, the disruption of normal cell architecture exposes claudin 18.2, making it a vulnerable therapeutic target. By binding to claudin 18.2, zolbetuximab-clzb activates the immune system to target and destroy cancer cells expressing this protein. This is the first FDA approval for any claudin 18.2-targeting therapy.
Pivotal Clinical Trials: SPOTLIGHT and GLOW
The FDA's decision was supported by data from two randomized, multicenter, double-blind phase III clinical trials: SPOTLIGHT and GLOW. Both trials enrolled patients with advanced unresectable or metastatic gastric or GEJ cancer that tested positive for claudin 18.2 expression.
In the SPOTLIGHT trial, 565 patients were randomized (1:1) to receive either mFOLFOX6 chemotherapy plus zolbetuximab-clzb or mFOLFOX6 plus placebo. The zolbetuximab-clzb arm demonstrated a 24.9% reduction in the risk of disease progression or death and a 25% reduction in the risk of death from any cause compared to the placebo arm.
The GLOW trial involved 507 patients randomized (1:1) to receive either CAPOX chemotherapy plus zolbetuximab-clzb or CAPOX plus placebo. Results showed a 31.3% decrease in the risk of disease progression or death and a 22.9% decrease in the risk of death from any cause in the zolbetuximab-clzb arm compared to the placebo arm.
Dosage and Administration
The recommended dose of zolbetuximab-clzb is based on body surface area, administered intravenously at 800 mg/m2 for the first dose, followed by either 600 mg/m2 every three weeks or 400 mg/m2 every two weeks for subsequent doses.
Disease Burden and Current Treatment Landscape
Gastric and GEJ cancers are malignancies of the digestive tract, with gastric cancer affecting the stomach lining and GEJ cancer affecting the junction between the stomach and esophagus. In 2024, an estimated 26,890 individuals in the United States were projected to be diagnosed with stomach cancer, and 10,880 were expected to die from the disease. This approval offers a new targeted therapy option for a subset of these patients, potentially improving outcomes in a challenging disease.
Companion Diagnostic
Alongside the approval of zolbetuximab-clzb, the FDA also approved a companion diagnostic test for claudin 18.2. This test is crucial for identifying patients who are most likely to benefit from zolbetuximab-clzb treatment, ensuring that the therapy is appropriately targeted to those with claudin 18.2-positive tumors.
