Astellas Pharma Inc. announced the European Medicines Agency (EMA) has accepted for regulatory review the company's marketing authorization application (MAA) for zolbetuximab, 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 tumours are CLDN18.2-positive. If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in Europe for these patients.
Gastric cancer accounted for 3.1% of all new cancer cases in Europe in 2020, with around 136,000 new cases diagnosed. The average five-year survival rate for patients with gastric cancer in Europe is 26% across all stages.
"Patients with gastric cancer in Europe face extremely low five-year survival rates regardless of their disease stage, and innovative therapies that extend survival are needed," said Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of immuno-oncology development, Astellas. "The EMA's acceptance of the zolbetuximab MAA continues a cascade of regulatory milestones for Astellas that are aimed at bringing a new option to patients with advanced gastric and GEJ cancer."
The MAA 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 tumours that were CLDN18.2-positive (=75% of tumour cells with moderate-to-strong membranous CLDN18 staining intensity), as determined by a validated immunohistochemistry assay.
The anticipated recommendation by the Committee for Medicinal Products for Human Use (CHMP) of the EMA regarding the MAA and subsequent European Commission (EC) decision are expected in calendar year 2024.
Astellas has already reflected the impact from this acceptance in its financial forecast of the current fiscal year ending March 31, 2024.
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide. Gastric cancer accounted for 3.1% of all new cancer cases in Europe in 2020, with around 136,000 new cases diagnosed. The average five-year survival rate for patients with gastric cancer in Europe is 26% across all stages. Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhoea or constipation, bloating of the stomach after meals, 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 tumour'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 Claudin 18.2 (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 and GEJ cancers, and there is no guarantee the agent will receive regulatory approval or become commercially available for the uses being investigated.
SPOTLIGHT is a phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours were CLDN18.2-positive. The study enrolled 565 patients at 215 study locations in the US, Canada, United Kingdom, Australia, Europe, South America and Asia. The primary endpoint is progression-free survival (PFS) in participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability and quality-of-life parameters.
Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19 and were subsequently published in The Lancet on April 14.
GLOW is a phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours were CLDN18.2-positive. The study enrolled 507 patients at 166 study locations in the US, Canada, United Kingdom, Europe, South America and Asia. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability and quality-of-life parameters.
Data from the GLOW study were initially presented at the March 2023 American Society of Clinical Oncology (ASCO) Plenary Series with an updated oral presentation at the 2023 ASCO Annual Meeting on June 3.
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 tumours (defined as =75% of tumour cells demonstrating moderate-to-strong membranous CLDN18 staining based on a validated immunohistochemistry assay).
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world.
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