Astellas’ Zolbetuximab Meets Phase 3 Endpoints In Gastric And GEJ Cancers

Zolbetuximab has met key endpoints in a Phase 3 trial in Claudin 18.2 (CLDN18.2)-positive, HER2-negative locally advanced or metastatic gastric and gastroesophageal junction (GEJ) cancers, drug developer Astellas announced Thursday.

The company is developing zolbetuximab as a first-line treatment for the subtype of gastric and GEJ cancers. The positive topline, together with good news from another Phase 3 called Spotlight, could provide the foundation for regulatory submissions worldwide. 

To date, there are no approved treatments that target CLDN18.2, a promising biomarker for gastric and GEJ cancers. However, a raft of therapies is in the global pipeline, including bispecific, CAR T-cells, and antibody-drug conjugates.

Related article: Astellas’ Claudin 18.2 Antibody Shows Its Teeth In GEJ Cancer Trial

Anti-CLDN18.2 Antibody 

Zolbetuximab, a chimeric IgG1 monoclonal antibody, targets CLDN18.2 to activate two immune system pathways: antibody-dependent cellular toxicity (ADCC) and complement-dependent cytotoxicity (CDC). The two events induce cancer cell death. 

CLDN18.2 is a transmembrane protein that helps regulate the flow of molecules at the epithelial tight junctions between gastric cells. It is often highly expressed in cancerous cells. In the Spotlight and Glow studies, approximately 38% of the patients have CLDN18.2-positive tumors as determined by a validated immunohistochemistry assay. 

In Glow, which enrolled 507 patients, a combination of zolbetuximab and CAPOX (a chemotherapy regimen containing capecitabine and oxaliplatin) led to a statistically significant improvement in progression-free survival (PFS) in treated patients compared to placebo plus CAPOX, meeting the primary endpoint. 

The combination also met the secondary endpoint of overall survival (OS). Other secondary endpoints include objective response rate and duration of response. The most common side effects resulting from the treatment were nausea and vomiting. 

The results and safety profile resemble the readout from Spotlight, which tested zolbetuximab with mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) against placebo plus mFOLFOX6. Detailed data from both trials will be presented at an upcoming scientific congress and submitted for publication.

The company intends to discuss the results with regulatory authorities, said Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Development Therapeutic Areas at Astellas.  

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Joy Lin

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