SUMMARY: The FDA on October 18, 2024, approved Zolbetuximab-clzb (VYLOY®), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. The FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with Gastric or GEJ adenocarcinoma who may be eligible for treatment with Zolbetuximab.
The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 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 (GEJ) 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 with metastatic disease is approximately 6%. These patients frequently are treated with platinum containing chemotherapy along with a fluoropyrimidine such as modified FOLFOX6 or CAPOX. 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.
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 on the surface of the cancer cells and accessible to targeted therapies with antibodies. CLDN18.2 is expressed in 30-40% of Gastric adenocarcinomas.
Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death.
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. This study met the Primary endpoint and the median Progression Free Survival (PFS) was 10.6 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 Overall Survival (OS) was also significantly improved (18.23 versus 15.54 months, HR=0.75; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population.
GLOW trial is a global, multi-center, double-blind, randomized Phase III study, conducted to assess the efficacy and safety of Zolbetuximab plus CAPOX (N=254) versus placebo plus CAPOX (N=253) as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. In this trial, 507 eligible patients were randomly assigned 1:1 to receive Zolbetuximab 800 mg/m2 IV as a loading dose on cycle 1, day 1, of the first 21-day cycle, followed by 600 mg/m2 IV on day 1 of subsequent cycles, along with CAPOX regimen consisting of Capecitabine 1000 mg/m2 orally twice daily on days 1-14 of each cycle and Oxaliplatin 130 mg/m2 IV on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both treatment groups and patients could continue beyond 8 cycles with Zolbetuximab or placebo plus Capecitabine at investigator’s decision, and treatment continued until disease progression or unacceptable toxicities. CLDN18.2 positive was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining and patients were stratified by region (Asia versus non-Asia), number of organs with metastases, and prior gastrectomy (yes versus no). The median patient age was 60 years, majority of patients were male from Asia, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1. Basline characteristics were similar in both treatment groups. The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.
At a median follow up of 12.6 months, the combination of Zolbetuximab plus CAPOX significantly improved PFS, and the median PFS was 8.2 months, compared with 6.8 months for those given placebo plus CAPOX (HR=0.68; P=0.0007). The median OS was 14.4 months versus 12.2 months respectively (HR=0.77; P=0.01). The PFS and OS benefits were sustained at 24 months, and the benefits were observed across most subgroups. The most common side effects were nausea and vomiting and the authors recommended increasing the infusion duration time, or splitting the dose over a 2 day period, in addition to the administration of prophylactic antiemetics.
The researchers concluded that the addition of first-line Zolbetuximab to CAPOX significantly improved PFS and OS in patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. The authors added that Zolbetuximab plus CAPOX represents a potential new first-line therapy for this patient group. Taken together, both GLOW and SPOTLIGHT trials showed a similar reduction in the risk of disease progression or death and a similar reduction in the risk of death with the addition of Zolbetuximab to chemotherapy, when compared with placebo plus chemotherapy.
Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Shah MA, Shitara K, Ajani JA, et al. Nature Medicine 2023; 29:2133–2141
