FDA Issues Complete Response Letter to Astellas for Zolbetuximab BLA for GEJ Adenocarcinoma

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The FDA has issued a complete response letter to Astellas Pharma Inc’s Biologics License Application (BLA) for zolbetuximab, which had a Prescription Drug User Fee Act (PDUFA) action date of January 12, 2024.¹ Astellas is seeking approval for the investigational, first-in-class Claudin (CLDN) 18.2 targeted monoclonal antibody for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN 18.2 positive.

The FDA stated that it is unable to approve the BLA by the PDUFA date because of unresolved deficiencies found in a pre-license inspection of a third-party manufacturing facility for the drug. The complete response letter was not related to clinical data for efficacy or safety for zolbetuximab and the agency is not requiring additional clinical studies, according to Astellas.

“We remain confident in zolbetuximab’s clinical profile and potential to fill a significant therapeutic gap for those diagnosed with advanced gastric or GEJ cancer whose tumors are CLDN18.2 positive,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development, Astellas, said in a press release. “Astellas is committed to working with the FDA and the third-party manufacturer to address the agency’s feedback, and to bringing zolbetuximab to US patients in need, as soon as possible.”¹

Zolbetuximab binds to Claudin 18.2, which is a transmembrane protein. During this process, the protein activates the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) pathways, which leads to cancer cell death.

In the Phase III SPOTLIGHT trial, zolbetuximab plus mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) were found to improve progression-free survival (PFS) in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma compared to placebo. The trial’s primary endpoint was PFS, with secondary endpoints of overall survival (OS), objective response rate, duration of response, safety, tolerability, and quality-of-life.²

Patients administered zolbetuximab showed statistically significant improvements in PFS and OS compared to placebo, with a 24.9% lower risk of progression or death. Median PFS was found to be 10.61 months in the zolbetuximab cohort vs. 8.67 months in the control group. Treatment-emergent adverse events (TEAEs) in the zolbetuximab arm vs. the placebo arm included nausea (82.4% and 60.8%, respectively), vomiting (67.4% and 35.6%, respectively), and decreased appetite (47.0% and 33.5%, respectively).

Gastric cancer is the fifth most diagnosed form of the disease. Early-stage symptoms of gastric cancer frequently overlap with the symptoms of common gastrointestinal conditions, such as gastroesophageal reflux disease, which leads to the disease commonly being diagnosed in the late and metastatic stage. Patients with late-stage disease have a relative survival rate of 6% at five years.²

Potential symptoms of gastric cancer include indigestion, abdominal pain or discomfort, nausea, vomiting, diarrhea, constipation, stomach bloating after eating, and appetite loss. Patients with advanced gastric cancer may experience unexplained weight loss, weakness, fatigue, vomiting of blood, or bloody stool.

In a press release, Astellas said it will work closely with the FDA and the third-party manufacturer to develop a timeline that will quickly resolve the feedback from the complete response letter. No other Astellas products were affected, according to the release.¹

References

1. Astellas Provides Update on Zolbetuximab Biologics License Application in U.S. Astellas Pharma Inc. News release. January 8, 2024. Accessed January 9, 2024. https://www.astellas.com/en/news/28731

2. Astellas to Present Positive Findings from Phase 3 SPOTLIGHT Trial of Zolbetuximab during 2023 ASCO GI Cancers Symposium. News Release. January 19, 2023. Accessed January 9, 2024. https://www.astellas.com/en/