The US Food and Drug Administration (FDA) has approved zolbetuximab (Vyloy, Astellas Pharma) in combination with fluoropyrimidine and platinum-containing chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma that is claudin 18.2 positive.

FDA also approved the Ventana CLDN18 (43-14A) RxDx Assay, from Ventana Medical Systems, Inc. and Roche Diagnostics, to identify claudin 18.2–positive tumors and thus patients who may be eligible to receive zolbetuximab.

Zolbetuximab is the first claudin 18.2–targeting agent approved in the United States. Approval of the monoclonal antibody was originally scheduled for earlier in the year but was delayed due to problems at a third-party manufacturing plant; those problems have since been resolved.

Zolbetuximab was also approved in Japan, Europe, and the United Kingdom earlier in the year. The company estimates that the global market will be about 82,000 patients annually.

“While there have been advances in the first-line treatment of locally advanced unresectable and metastatic gastric and GEJ cancers in the last several years, there is still a tremendous unmet need among our patients,” Samuel J. Klempner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in a company press release. The approval of zolbetuximab “brings forward a novel biomarker and new therapy for patients whose tumors are CLDN18.2 positive, and for those on the frontlines of treatment decision-making.”

Claudin 18.2 — a cell surface protein prominent in the stomach lining and associated with tumor growth and progression — is overexpressed in about 40% of gastric and gastroesophageal junction tumors. Zolbetuximab binds claudin 18.2 and triggers immune responses that kill the cancer cells.

The FDA approval was based on two international phase 3 trials — SPOTLIGHT and GLOW.

Across the 565 patients in SPOTLIGHT, adding zolbetuximab to mFOLFOX6 chemotherapy led to a significant improvement in median overall and progression-free survival. Patients who received zolbetuximab with mFOLFOX6 chemotherapy demonstrated a median overall survival benefit of almost 3 months — 18.2 months in the zolbetuximab-chemotherapy arm vs 15.5 months in the chemotherapy-placebo group (hazard ratio [HR], 0.750). Median progression-free survival was 10.6 months in the zolbetuximab plus mFOLFOX6 arm vs 8.7 months in mFOLFOX6 plus placebo arm (HR, 0.751).

In GLOW, 507 patients were randomly assigned to either zolbetuximab with CAPOX chemotherapy or placebo with CAPOX. Adding zolbetuximab to CAPOX also led to a significant improvement in overall and progression-free survival. Median overall survival was 14.4 months in the zolbetuximab arm vs 12.2 months in the CAPOX-only group (HR, 0.771), and median progression-free survival was 8.2 months in the zolbetuximab arm vs 6.8 months in the CAPOX-only group (HR, 0.687).

The incidence of serious adverse events was similar between the zolbetuximab and placebo arms in both trials. Nausea, vomiting, and decreased appetite were the most common side effects, and were substantially more likely with zolbetuximab add-on.

The recommended zolbetuximab dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m² intravenously for the first dose, and 600 mg/m² intravenously every 3 weeks or 400 mg/m² intravenously every 2 weeks for subsequent doses.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]