Astellas Submits NDA for Global First-in-Class CLDN18.2 Monoclonal Antibody Zolbetuximab in Japan

On June 9, Astellas announced that it had submitted a new drug application for the CLDN18.2 monoclonal antibody zolbetuximab to Japan's Ministry of Health, Labour and Welfare for the first-line treatment of CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. If approved, zolbetuximab will become the world’s first approved CLDN18.2-targeted therapy.

Zolbetuximab is a first-in-class monoclonal antibody independently developed by Ganymed (a subsidiary of Astellas) that targets Claudin 18.2 (CLDN18.2) and can specifically recognize and bind to CLDN18.2. Claudin 18.2 is a member of the claudin protein family, primarily expressed in gastric epithelial cells and highly expressed in primary malignant tumors such as gastric cancer, breast cancer, colon cancer, and liver cancer. Preclinical studies have shown that zolbetuximab induces cancer cell death by activating two different immune system pathways: antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

This NDA is based on the results of the Phase III SPOTLIGHT and GLOW clinical trials.

SPOTLIGHT Study Evaluates the Efficacy and Safety of Zolbetuximab Combined with mFOLFOX6 (a Combination Regimen Including Oxaliplatin, Leucovorin, and Fluorouracil) as First-Line Treatment for CLDN18.2-Positive, HER2-Negative Locally Advanced Unresectable or Metastatic G/GEJ Adenocarcinoma Patients. The Results Showed that the Combination of Zolbetuximab and mFOLFOX6 Achieved Statistically Significant Improvements in Progression-Free Survival (PFS) and Overall Survival (OS) Compared to Placebo Combined with mFOLFOX6.

Specifically, compared to the placebo group, the combination of zolbetuximab and mFOLFOX6 reduced the risk of disease progression or death by 24.9% (n=565; hazard ratio [HR]=0.751; [95% confidence interval [CI]: (0.598-0.942)]; P-value=0.0066), reaching the primary endpoint of the SPOTLIGHT study. The median PFS in the treatment group was 10.61 months (95% CI: 8.90-12.48), compared to 8.67 months (95% CI: 8.21-10.28) 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% (hazard ratio=0.750; 95% CI: 0.601-0.936; P value=0.0053). The median OS in the treatment group and placebo group was 18.23 months (95% CI: 16.43-22.90) and 15.54 months (95% CI: 13.47-16.53), respectively.

The GLOW study compared 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 the Zolbetuximab group extended PFS by 1.4 months and OS by 2.2 months. Additionally, the objective response rates (ORR) were 53.8% and 48.8%, respectively, and the mDORs were 6.28 months and 6.18 months, showing no significant difference.

In the study regarding serious adverse events (TEAEs) during treatment, the incidence rates in the two groups were similar (47.2% in the Zolbetuximab group vs. 49.8% in the placebo group), consistent with previous research. During the GLOW study, the most common serious adverse events during treatment in the Zolbetuximab group versus the placebo group were nausea (68.5% vs. 50.2%), vomiting (66.1% vs. 30.9%), and decreased appetite (41.3% vs. 33.7%).

Dr. Pranob Bhattacharya, Executive Director and Interim Head of Immuno-Oncology Development at Astellas, stated: "Gastric cancer remains the third leading cause of cancer-related deaths in Japan. Despite significant progress in reducing the impact of this disease, it still results in approximately 50,000 deaths annually. Astellas' submission of a New Drug Application for zolbetuximab to Japan's Ministry of Health, Labour and Welfare demonstrates the company’s commitment to addressing the unmet needs of gastric cancer patients in Japan."

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