Astellas Pharma Inc. has submitted a new drug application (NDA) to the Japanese Ministry of Health, Labor and Welfare (MHLW) for zolbetuximab.
Zolbetuximab is a first-in-class, investigated Claudin 18.2 (CLDN18.2) targeted monoclonal antibody, for the first-line treatment of patients with inoperable HER2-negative or locally advanced inoperable adenocarcinoma of the stomach or gastroesophageal junction (GEJ) whose tumor is CLDN18. 2-positive.
If approved, zolbetuximab will be the first CLDN18.2 targeted therapy available in Japan for these patients.
“Stomach cancer remains the third deadliest cancer in Japan, causing around 50,000 deaths a year despite significant steps 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 SPOTLIGHT and GLOW phase 3 clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) versus placebo plus mFOLFOX6. The GLOW study evaluated zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) versus placebo plus CAPOX.
In SPOTLIGHT and GLOW, approximately 38% of patients screened for the trial had CLDN18.2-positive tumors (≥75% of tumor cells with moderate to strong membrane CLDN18 staining intensity), as determined by a validated immunohistochemical assay.
Stomach cancer, also known as stomach cancer, is the fifth most frequently diagnosed cancer worldwide. Stomach cancer kills 50,000 people a 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 stomach, nausea and vomiting, diarrhea or constipation, flatulence after eating and loss of appetite and the sensation of food getting stuck in the throat when eating. Signs of more advanced stomach cancer can include unexplained weight loss, weakness and fatigue, and vomiting blood or having blood in the stool.
Risk factors associated with stomach cancer can include older age, male gender, family history, H. pylori infection, smoking, and gastroesophageal reflux disease (GERD). Because the symptoms of early-stage stomach cancer often overlap with more common stomach-related conditions, stomach cancer is often diagnosed at an advanced or metastatic stage, or after it has spread from the tumor’s origin to other tissues or organs of the body. The five-year relative survival rate for patients at the metastatic stage is 6.6%. Gastroesophageal junction (GEJ) adenocarcinoma is cancer that starts in the area where the esophagus joins the stomach.
Zolbetuximab is the first in its class of chimeric IgG1 monoclonal antibody (mAb) under study that targets and binds to CLDN18.2, a transmembrane protein. Zolbetuximab works by binding to CLDN18.2 on the surface of gastric epithelial cancer cells. In pre-clinical studies, these binding interactions then induce cancer cell death by activating two distinct pathways of the immune system – antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Zolbetuximab has not been approved by any regulatory agency for the treatment of patients with gastric, GEJ and pancreatic cancer and there is no guarantee that the agent will receive regulatory approval or be commercially available for the use under investigation.
An expanded phase 2 trial in metastatic pancreatic adenocarcinoma is ongoing. This trial is an open label, multi-center, randomized study evaluating the safety and efficacy of the studied zolbetuximab in combination with gemcitabine plus nab-paclitaxel as first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2-positive tumors (defined as as ≥75% of tumor cells showing moderate to strong membrane CLDN18 staining based on validated immunohistochemical assay).
In addition to zolbetuximab, ASP2138 is under development. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and Claudin 18.2, and is currently in phase 1 trials in people with gastric, gastroesophageal junction or pancreatic cancer. The safety and efficacy of the agents under investigation have not been established for the use under consideration.
In addition to cancer, Astellas recently signaled its intention to move into ophthalmology with its $5.9 billion acquisition of Iveric Bio.