China NMPA accepts Astellas BLA for zolbetuximab to treat patients with locally advanced unresectable or metastatic HER2-negative gastric GEJ adenocarcinoma

Astellas Pharma Inc. announced that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the Biologics License Application (BLA) 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 China for these patients.

Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of immuno-oncology development, Astellas, said: “China accounts for nearly half of the world’s new cases of gastric cancer, with more than 478,000 new cases diagnosed and more than 373,000 deaths in 2020. The CDE’s acceptance of our BLA for zolbetuximab brings us one step closer to having a new therapy available for Chinese patients with advanced-stage disease and in need of treatment options.”

The BLA is based on results from the phase 3 GLOW and SPOTLIGHT clinical trials. The GLOW study evaluated zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX. In the GLOW study, 145 patients were randomized in mainland China. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6. In the SPOTLIGHT study, 36 patients were randomized in mainland China.

In both GLOW and SPOTLIGHT, 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.

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. In China, gastric cancer ranks third among incidences of all cancer, with more than 478,000 cases diagnosed and more than 373,000 deaths in 2020. 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.

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, including China. The primary endpoint is progression-free survival (PFS) in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. 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 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.

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, including China. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include OS, ORR, 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.

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-tostrong membranous CLDN18 staining based on a validated immunohistochemistry assay).

In addition to zolbetuximab, ASP2138 is under development in our Primary Focus Immuno-Oncology. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and CLDN18.2, and it is currently in a phase 1 trial for people with gastric, GEJ or pancreatic adenocarcinoma. The safety and efficacy of the agent under investigation have not been established for the uses being considered.

Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world.

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