The Role of cMET in Gastric Cancer—A Review of the Literature

SIMPLE SUMMARY: cMET is a proto-oncogene that has been extensively studied in gastric cancer. Gastric cancer (GC) is a heterogenous disease with varied histology and molecular profiling. It still implies a poor prognosis in stage IV. New targeted therapeutic options are being investigated. In this review, we analyzed all studies performed on gastric cancer with MET-inhibitors. In first-line therapy, the addition of MET-inhibition to chemotherapy did not show any benefit in allcomers. Different tyrosine kinase inhibitors (TKI) have been investigated in small cohorts with different diagnostic assays added to the inclusion criteria. Determining patients with gastric cancer who benefit from cMET inhibitors remains difficult. Potentially only MET amplification detected by comprehensive genomic testing could be a good targeted option, although the prevalence is limited to less than 5% of all patients with gastric cancer. ABSTRACT: Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the introduction of targeted therapies against HER2 and with checkpoint inhibitors (PDL1). More agents interfering with other targets (FGFR2B, CLDN18.2) are being investigated. cMET is a less frequent molecular target that has been studied for gastric cancer. It is a proto-oncogene that leads to activation of the MAPK pathway and the PI3K pathway, which is responsible for activating the MTOR pathway. The prevalence of cMET is strongly debated as different techniques are being used to detect MET-driven tumors. Because of the difference in diagnostic assays, selecting patients who benefit from cMET inhibitors is difficult. In this review, we discuss the pathway of cMET, its clinical significance and the different diagnostic assays that are currently used, such as immunohistochemy (IHC), fluorescence in situ hybridization (FISH), the H-score and next-generation sequencing (NGS). Next, we discuss all the current data on cMET inhibitors in gastric cancer. Since the data on cMET inhibitors are very heterogenous, it is difficult to provide a general consensus on the outcome, as inclusion criteria differ between trials. Diagnosing cMET-driven gastric tumors is difficult, and potentially the only accurate determination of cMET overexpression/amplification may be next-generation sequencing (NGS).