Astellas Pharma Inc. has announced the U.S. Food and Drug Administration (FDA) acknowledged the resubmission of its Biologics License Application (BLA) for zolbetuximab. This investigational drug is intended as a first-line treatment for adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive. The FDA has set a new target action date of November 9, 2024, under the Prescription Drug User Fee Act (PDUFA). If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in the U.S. for this patient population.
Clinical Significance
Gastric cancer remains a significant global health challenge. In the U.S. alone, estimates suggest approximately 26,890 new diagnoses and 10,880 deaths from gastric cancer in 2024. Early-stage symptoms often overlap with common stomach conditions, leading to diagnoses at advanced stages where the five-year survival rate is only 7% for metastatic cases. Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Senior Vice President and Head of Immuno-Oncology Development at Astellas, emphasized the unmet needs of patients with advanced gastric or GEJ cancer and the potential of zolbetuximab to address this critical gap.
Regulatory Background
The zolbetuximab BLA was initially submitted but faced a complete response letter from the FDA on January 4, 2024, due to manufacturing deficiencies identified at a third-party facility. The FDA did not raise concerns regarding the clinical data related to efficacy or safety and did not request additional clinical studies.
Pivotal Clinical Trials
The resubmission is based on data from the Phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study assessed zolbetuximab plus mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) against placebo plus mFOLFOX6. The GLOW study evaluated zolbetuximab plus CAPOX (capecitabine and oxaliplatin) compared to placebo plus CAPOX. Approximately 38% of screened patients in both trials had CLDN18.2-positive tumors, defined as ≥75% of tumor cells showing moderate-to-strong membranous CLDN18 staining via a validated immunohistochemistry assay.
Zolbetuximab: Mechanism of Action
Zolbetuximab is a first-in-class investigational monoclonal antibody (mAb) that targets and binds to CLDN18.2, a transmembrane protein. Pre-clinical studies indicated that zolbetuximab depletes CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Global Regulatory Landscape
On March 26, 2024, Japan's Ministry of Health, Labour and Welfare (MHLW) approved zolbetuximab, making it the first CLDN18.2-targeted treatment for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer. Astellas has also submitted applications to other regulatory agencies, with reviews currently ongoing.
Ongoing Research
Astellas is also investigating zolbetuximab in a Phase 2 trial for metastatic pancreatic adenocarcinoma, evaluating its combination with gemcitabine plus nab-paclitaxel as a first-line treatment for patients with CLDN18.2-positive tumors. Additionally, ASP2138, a bispecific monoclonal antibody targeting CD3 and CLDN18.2, is in Phase 1/1b study for gastric, GEJ, or pancreatic adenocarcinoma with CLDN18.2 expression.
