Astellas Scores Late-Phase Win in CLDN18.2-Positive Gastric Cancer (Updated)

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Astellas' Phase III SPOTLIGHT trial studying zolbetuximab in CLDN18.2-positive, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma returned positive results, the company reported Wednesday. 

Zolbetuximab, a first-in-class chimeric IgG1 monoclonal antibody, targets the transmembrane protein CLDN18.2, which was first discovered by Ugur Sahin and Özlem Türeci. The two would later go on to found BioNTech. 

The trial, which evaluated 566 patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, hit its primary endpoint. 

Statistical significance in progression-free survival was seen in patients receiving the drug plus the combination cancer treatment known as mFOLFOX6, which is made up of oxaliplatin, leucovorin and fluorouracil.

CLDN18.2 is an isoform (functionally similar) of claudin18, part of a family of tight junction proteins. CLDN18.2 has limited expression in normal tissues but is often seen in high levels in certain primary malignant cancers. It is involved in the proliferation, differentiation and metastases of cancer cells.

Based on the trial, about 38% of patients screened had CLDN18.2-positive tumors. Prior to the discovery of CLDN18.2, a limiting factor to developing effective targeted drugs for gastric cancer was the lack of appropriate biomarkers.

In addition to the primary endpoint of PFS, the trial also met a secondary endpoint of overall survival, demonstrating statistical significance for patients receiving zolbetuximab and mFOLFOX6 compared to placebo plus mFOLFOX6.

“Gastric and GEJ cancers still have very limited treatment options available for patients with an advanced diagnosis,” said Kohei Shitara, M.D., primary investigator for the SPOTLIGHT trial and chief, department of gastrointestinal oncology at the National Cancer Center Hospital East in Kashiwa, Japan in a statement. 

Astellas is also studying zolbetuximab plus CAPOX (capecitabine and oxaliplatin) in the Phase III GLOW study. GLOW is evaluating zolbetuximab plus CAPOX as first-line treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

“SPOTLIGHT is the first Phase III pivotal trial to validate CLDN18.2 as a target for gastric cancer” which is “very significant," Ahsan Arozullah, SVP and head of development therapeutic areas for Astellas told BioSpace in an interview.

The most common treatment-emergent adverse events in patients receiving zolbetuximab and mFOLFOX6 in the trial were nausea, vomiting and loss of appetite.

Arozullah said Astellas will determine next steps for discussions with regulators in the U.S., Europe, Japan and other countries “based on the results from SPOTLIGHT and GLOW.” 

To date, no therapeutics have been approved targeting CLDN18.2. According to ClinicalTrials.gov, there were 54 trials targeting the molecule. Most are in solid tumors, including advanced unresectable GC, GEJ, metastatic esophageal cancer and pancreatic cancer.