Phase 3 Trial Showed Zolbetuximab Significantly Improved Survival In Patients with Metastatic Gastric, Gastroesophageal Cancers

Zolbetuximab treatment reduced risk of death by 25% compared to placebo.

Based on the results of the phase 3 SPOTLIGHT trial, zolbetuximab (Astellas Pharma), an investigational first-in-class Claudin 18.2 (CLDN18.2) targeted monoclonal antibody, and mFOLFOX6, a combination regimen of oxaliplatin, leucovorin, and fluorouracil, were found to increase progression-free survival (PFS) in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, compared to placebo. During the trial, PFS was the primary endpoint for the treatment arm, with secondary endpoints of overall survival (OS), objective response rate (ORR), duration of response (DoR), safety, tolerability, and quality-of-life.

Gastric cancer, also known as stomach cancer, is the number 5 most diagnosed cancer. Early-stage gastric cancer symptoms often overlap with symptoms of common stomach-related issues like gastroesophageal reflux disease (GERD), so diagnosis is often late-stage and metastatic. GEJ adenocarcinoma affects the area where the esophagus joins the gut; with late-stage disease, patients have a relative survival rate of 6% at 5 years.

"For gastric and gastroesophageal junction cancer patients with disease that is locally advanced but inoperable or metastatic, to see a positive progression-free and overall survival response in SPOTLIGHT is very encouraging given the limited treatment options available," said primary trial investigator Kohei Shitara, MD, chief of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East in Kashiwa, Japan, in the press release.

Zolbetuximab targets and binds to Claudin 18.2, a transmembrane protein. During this process, the protein activates the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) pathways, inducing cancer cell death.

Zolbetuximab was evaluated as a first-line treatment for patients with CLDN18.2 positive, HER2- negative, locally advanced unresectable or metastatic gastric or GEJ cancer in SPOTLIGHT, which was a phase 3 global, multi-center, double-blind, and randomized study. In total, ttthe study included 565 patients across 5 continents who either received zolbetuximab and mFOLFOX6, or placebo and mFOLFOX6.

Patients in the zolbetuximab arm showed statistically significant improvements in PFS and OS compared to the placebo arm, having a reduced risk of progression or death by 24.9%. Additionally, the median PFS was 10.61 months in the zolbetuximab arm compared to 8.67 months in the control arm.

The zolbetuximab and control groups experienced common treatment-emergent adverse events (TEAEs), including nausea (82.4% and 60.8%), vomiting (67.4% and 35.6%), and decreased appetite (47.0% and 33.5%).

Symptoms of gastric cancer may include indigestion (heartburn), abdominal pain or discomfort, nausea, vomiting, diarrhea or constipation, stomach bloating after meals, loss of appetite, and feeling like food is lodged in the throat while eating. Patients with more advanced gastric cancer may experience unexplained weight loss, weakness, fatigue, vomiting blood, or a bloody stool.

The clinical data was presented alongside data from the GLOW study. GLOW was a phase 3 multi-center, double-blind, randomized study, that evaluated efficacy and safety of zolbetuximab with the combination of capecitabine and oxaliplatin (CAPOX) against placebo plus CAPOX. The findings of both GLOW and SPOTLIGHT were presented at the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.

"The investigational results from SPOTLIGHT are exciting and support the potential of zolbetuximab as a precision therapy for patients with CLDN18.2-positive gastric/GEJ cancer," said Ahsan Arozullah, MD, MPH, senior vice president and head of development therapeutic areas, Astellas, in the press release.


Astellas to Present Positive Findings from Phase 3 SPOTLIGHT Trial of Zolbetuximab during 2023 ASCO GI Cancers Symposium. News Release. January 19, 2023. Accessed January 23, 2023.

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