Companion Diagnostics and Predictive Biomarkers for MET-Targeted Therapy in NSCLC

SIMPLE SUMMARY: MET is a receptor tyrosine kinase encoded by the MET proto-oncogene that has a significant role in cancer cell progression. Several drugs targeting MET are under development for the treatment of different cancers, including non-small-cell lung cancer (NSCLC). However, until now, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective biomarkers to select the right patients for treatment. In a number of clinical trials, different biomarkers have been studied, but so far, MET exon 14 skipping mutation is the only one that has shown sufficient predictive properties. Another interesting biomarker is MET amplification detected by fluorescence in situ hybridization (FISH), which has shown promising results in the treatment of patients with NSCLC. Future clinical research will show whether MET amplification by FISH is an effective predictive biomarker for MET-targeted therapy. ABSTRACT: Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell lung cancer (NSCLC). However, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective predictive biomarkers to select the right patient populations for treatment. So far, capmatinib is the only MET-targeted drug approved with a companion diagnostic (CDx) assay, which is indicated for the treatment of metastatic NSCLC in patients having a mutation resulting in MET exon 14 skipping. An alternative predictive biomarker for MET therapy is MET amplification, which has been identified as a resistance mechanism in patients with EGFR-mutated NSCLC. Results obtained from different clinical trials seem to indicate that the MET/CEP7 ratio detected by FISH possesses the best predictive properties, likely because this method excludes MET amplification caused by polysomy. In this article, the concept of CDx assays will be discussed, with a focus on the currently FDA-approved MET targeted therapies for the treatment of NSCLC.