The U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review to Astellas Pharma Inc.'s Biologics License Application (BLA) for zolbetuximab, a first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody. If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in the United States for patients with advanced gastric and gastroesophageal junction (GEJ) cancers.
Addressing Unmet Needs in Gastric Cancer
Gastric cancer, also known as stomach cancer, is the fifth most diagnosed cancer worldwide. In the U.S., approximately 26,500 new cases are expected in 2023, with 11,130 deaths. The five-year survival rate for metastatic gastric cancer is only 6.6%, highlighting the urgent need for new treatment options. Early-stage gastric cancer symptoms often overlap with more common stomach conditions, leading to diagnoses at advanced stages.
Mechanism of Action
Zolbetuximab is designed for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2-positive. The drug binds to CLDN18.2 on the surface of gastric epithelial cancer cells, inducing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Clinical Trial Data
The BLA is based on data from the Phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) compared to placebo plus mFOLFOX6. The GLOW study assessed zolbetuximab plus CAPOX (capecitabine and oxaliplatin) versus placebo plus CAPOX. Approximately 38% of screened patients in both studies had CLDN18.2-positive tumors, as determined by a validated immunohistochemistry assay. The SPOTLIGHT study demonstrated that the combination of zolbetuximab with mFOLFOX6 helped patients with claudin 18.2-positive, HER2-negative gastric or GEJ tumors live longer without their disease progressing than the chemo alone and also improved overall survival.
Regulatory Pathway and Future Outlook
The FDA reviewed the application under its Real-Time Oncology Review (RTOR) program, aimed at expediting the availability of safe and effective treatments. The Prescription Drug User Fee Act (PDUFA) target action date is January 12, 2024. Astellas is already scaling up commercial manufacturing capacity for zolbetuximab in anticipation of potential approval. The FDA has previously granted Fast Track designation to zolbetuximab for the treatment of gastric and GEJ adenocarcinoma.
Moitreyee Chatterjee-Kishore, senior vice president and head of immuno-oncology development at Astellas, stated that the FDA’s acceptance of the BLA filing and Priority Review designation for zolbetuximab confirms the urgent therapeutic need.
