Astellas Submits NDA in China for Zolbetuximab, a First-in-Class Anti-CLDN18.2 Monoclonal Antibody for Gastric and GEJ Adenocarcinoma

On August 1, the CDE website showed that Astellas' Zolbetuximab injection marketing application was accepted for the treatment of patients with gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma. This is the first CLDN18.2 monoclonal antibody to be submitted for marketing in China. Additionally, Zolbetuximab has been submitted for marketing in the United States, Europe, and Japan.

Zolbetuximab is a first-in-class investigational chimeric IgG1 monoclonal antibody targeting CLDN18.2, a transmembrane protein, with which it binds. Zolbetuximab exerts its effect by binding to CLDN18.2 on the surface of gastric cancer cells. Preclinical studies have shown that this binding subsequently induces cancer cell death by activating two distinct immune system pathways—antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

The new drug application is primarily based on the results of two Phase III clinical trials: the SPOTLIGHT study and the GLOW study.

SPOTLIGHT Study: Evaluating the Efficacy and Safety of Zolbetuximab Combined with mFOLFOX6 (a Regimen Including Oxaliplatin, Leucovorin, and Fluorouracil) as First-Line Treatment in CLDN18.2-Positive, HER2-Negative Patients with Locally Advanced Unresectable or Metastatic G/GEJ Adenocarcinoma.

The results showed that, compared with the placebo combined with mFOLFOX6 group, the combination of zolbetuximab and mFOLFOX6 achieved statistically significant improvements in progression-free survival (PFS) and overall survival (OS). Specifically, compared with the placebo group, the combination of zolbetuximab and mFOLFOX6 reduced the risk of disease progression or death by 24.9%, reaching the primary endpoint. The median PFS was 10.61 months in the treatment group and 8.67 months in the placebo group.

The study also showed that the combination of zolbetuximab and mFOLFOX6 significantly prolonged OS, reducing the risk of death by 25.0%. The median OS for the treatment group and placebo group were 18.23 months and 15.54 months, respectively.

In the study regarding the incidence of serious adverse events (TEAEs) during treatment, the incidence rates in the zolbetuximab group and the placebo group were similar (44.8% vs. 43.5%), consistent with previous studies. The most common adverse events during treatment were nausea (82.4% vs. 60.8%), vomiting (67.4% vs. 35.6%), and decreased appetite (47.0% vs. 33.5%).

The GLOW study aims to evaluate the efficacy of Zolbetuximab + CAPOX (capecitabine + oxaliplatin) versus placebo + CAPOX in 507 treatment-naïve G/GEJ adenocarcinoma patients with high CLDN18.2 expression (expression level ≥75%).

The results showed that, compared with the placebo plus CAPOX group, the combination of zolbetuximab and CAPOX achieved a statistically significant improvement in PFS. Specifically, compared with the placebo plus CAPOX group, the combination of zolbetuximab and CAPOX reduced the risk of disease progression or death by 31.3%, reaching the primary endpoint of the GLOW study. The median progression-free survival was 8.21 months in the treatment group and 6.80 months in the placebo group.

The study also showed that zolbetuximab in combination with CAPOX significantly prolonged OS at the key secondary endpoint, reducing the risk of death by 22.9%. The median overall survival was 14.39 months in the treatment group and 12.16 months in the placebo group.

In terms of treatment-emergent adverse events (TEAEs) during the treatment period, the incidence rates were similar between the two groups, with 47.2% in the zolbetuximab group vs. 49.8% in the placebo group, consistent with previous studies. During the GLOW study, the most common treatment-emergent adverse events in the zolbetuximab group compared to the placebo group were nausea (68.5% vs. 50.2%), vomiting (66.1% vs. 30.9%), and decreased appetite (41.3% vs. 33.7%).

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