Astellas Receives Complete Response Letter from FDA for Zolbetuximab in CLDN18.2-Positive Gastric/GEJ Adenocarcinoma

On January 9, Astellas announced that it had received a Complete Response Letter from the FDA regarding the BLA for zolbetuximab, a CLDN18.2 antibody, for the first-line treatment of CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

FDA States That Zolbetuximab Cannot Be Approved for Marketing Before the PDUFA Date of January 12, 2024, Due to Unresolved Deficiencies at Third-Party Manufacturing Plant. The FDA has not raised any concerns regarding the clinical data of zolbetuximab (including efficacy or safety) and has not requested additional clinical studies.

Zolbetuximab is a first-in-class monoclonal antibody independently developed by Ganymed, a subsidiary of Astellas, targeting CLDN18.2. CLDN18.2 is primarily expressed in gastric epithelial cells and is 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 marketing application is primarily based on the positive results from two Phase III studies, SPOTLIGHT and GLOW.

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 Gastric/Gastroesophageal Junction Adenocarcinoma.

Results showed that, compared with the placebo plus 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 of the study. 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.

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) for the two groups were 53.8% and 48.8%, respectively; the mDOR for the two groups were 6.28 months and 6.18 months, respectively, without showing significant differences.

In terms of treatment-emergent serious adverse events (TEAEs), 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 serious adverse events in the zolbetuximab group vs. 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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