Astellas recently announced positive top-line results of the Phase III SPOTLIGHT clinical trial designed to evaluate the efficacy and safety of zolbetuximab in combination with mFOLFOX6—a combination regimen including oxaliplatin, calcium folinate, and fluorouracil. Zolbetuximab is an investigational first-in-class monoclonal antibody against Claudin 18.2 (CLDN18.2) for the first-line treatment of patients with Claudin 18.2-positive, HER2-negative, locally advanced or metastatic gastric and gastroesophageal junction (GEJ) cancers.
The SPOTLIGHT clinical trial enrolled 566 Claudin 18.2-positive, HER2-negative patients with locally advanced or metastatic gastric cancer and gastroesophageal junction cancer and met its primary endpoint of statistically significant progression-free survival for patients treated with zolbetuximab and mFOLFOX6 compared to placebo and mFOLFOX6. In addition, the study met another secondary endpoint—overall survival—statistically significant for patients treated with zolbetuximab and mFOLFOX6 compared to placebo and mFOLFOX6. For patients treated with zolbetuximabin combination with mFOLFOX6, the most common adverse events included nausea, vomiting, and loss of appetite. Detailed results will be presented at a future academic conference.
“I am very excited that we have the potential to discover a novel treatment option for patients with advanced gastric or gastroesophageal junction cancer,” said Kohei Shitara, M.D., principal investigator of the SPOTLIGHT trial and head of the Department of Gastroenterology Cancer Division at the National Cancer Center in Japan. “For patients with advanced gastric or gastroesophageal junction cancer, the currently available treatment options are relatively limited.”
“We are very excited about the positive top-line results of the Phase III SPOTLIGHT clinical trial of zolbetuximab in combination with mFOLFOX6 and are even more confident with continuing to advance zolbetuximab as a first-line therapy for patients with locally advanced or metastatic gastric cancer. This top-line result further demonstrates the utilization of CLDN18.2 as a novel biomarker to treat gastric cancer and the gastroesophageal junction cancer,.” said Ahsan Arozullah, M.D., M.P.H., senior vice president, and head of Therapeutic Area Development at Astellas. “We look forward to presenting detailed results at an academic conference in the near future.”
Zolbetuximab works by binding to CLDN18.2 on the surface of gastric cancer epithelial cells. Preclinical studies have shown that this binding action subsequently induces cancer cell death through the activation of two distinct immune system pathways—antibody-dependent cellular-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). CLDN18.2 is a transmembrane protein found on normal gastric cells and a major component of the tight epithelial and endothelial junctions controlling the flow of molecules between cells. Preclinical studies have shown that CLDN18.2 is also expressed in gastric cancer and that, as gastric cancer progresses, CLDN18.2 may become aberrantly highly expressed and a target for targeted therapy. Based on this study, approximately 38% of screened patients were CLDN18.2 positive and ≥75% of tumor cells showed moderate to strong staining intensity CLDN18.2 expression based on validated immunohistochemical assay analysis.
The SPOTLIGHT Phase III clinical trial is a global, multicenter, double-blind, and randomized study designed to evaluate the efficacy and safety of the zolbetuximab and mFOLFOX6 combination compared to the placebo and mFOLFOX6 control group. Specifically, this study and the Phase III GLOW trial, which is designed to evaluate the efficacy and safety of zolbetuximab + capecitabine and oxaliplatin (CAPOX regimen) compared to the placebo and CAPOX regimen control arm, are being conducted to provide baseline data for regulatory submissions in the US, Europe, Asia, and other countries arou