SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%.
These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor or checkpoint inhibitor alone if the tumors express PD-L1.
Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.
SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.
This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.
The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.
Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292
