Astellas Pharma Inc. has submitted a new drug application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for zolbetuximab.
Zolbetuximab is a first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody, for first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive.
If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in Japan for these patients.
“Gastric cancer remains the third deadliest cancer in Japan, leading to approximately 50,000 deaths per year despite significant strides to reduce the impact of this cancer,” said Pranob Bhattacharya, executive director and interim head of immuno-oncology development at Astellas.
The NDA is based on results from the phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6. The GLOW study evaluated zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX.
In both SPOTLIGHT and GLOW, approximately 38% of patients screened for the trials had tumors that were CLDN18.2-positive (≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining intensity), as determined by a validated immunohistochemistry assay.
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide. Gastric cancer kills 50,000 people per year in Japan, making it the third deadliest cancer by number of deaths in the country. Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhea or constipation, bloating of the stomach after meals and loss of appetite and sensation of food getting stuck in the throat while eating. Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue and vomiting blood or having blood in the stool.
Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastroesophageal reflux disease (GERD). Because early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor’s origin to other body tissues or organs. The five-year relative survival rate for patients at the metastatic stage is 6.6%. Gastroesophageal junction (GEJ) adenocarcinoma is a cancer that starts at the area where the esophagus joins the stomach.
Zolbetuximab is an investigational, first-in-class chimeric IgG1 monoclonal antibody (mAb) that targets and binds to CLDN18.2, a transmembrane protein. Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways — antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Zolbetuximab has not been approved by any regulatory bodies for the treatment of patients with gastric, GEJ and pancreatic cancers and there is no guarantee the agent will receive regulatory approval or become commercially available for the uses being investigated.
An expanded phase 2 trial in metastatic pancreatic adenocarcinoma is in progress. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2-positive tumors (defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining based on a validated immunohistochemistry assay).
In addition to zolbetuximab, ASP2138 is under development. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and Claudin 18.2, and it is currently in a phase 1 trial for people with gastric, gastroesophageal junction or pancreatic cancer. The safety and efficacy of the agents under investigation have not been established for the uses being considered.
As well as cancer, Astellas recently signaled its intent to move into ophthalmology with the $5.9 billion acquisition of Iveric Bio.