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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Companion Diagnostics and Predictive Biomarkers for MET-Targeted Therapy in NSCLC
Jan Trøst Jørgensen1, Jens Mollerup2
1Department: Medical Sciences, Dx-Rx Institute, Baunevaenget 76, 3480 Fredensborg, Denmark.
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.
Insights
Identifying effective predictive biomarkers is crucial for MET-targeted therapies in non-small cell lung cancer (NSCLC). Companion diagnostic (CDx) assays, like those for MET exon 14 skipping, are key for patient selection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Dysregulation of the MET tyrosine kinase receptor drives oncogenesis in various cancers.
- MET-targeted therapies are under development for non-small cell lung cancer (NSCLC), but clinical success is limited.
- Effective predictive biomarkers are needed to optimize patient selection for MET-targeted treatments.
Purpose of the Study:
- To discuss the concept of companion diagnostic (CDx) assays.
- To focus on FDA-approved MET-targeted therapies for NSCLC.
- To highlight the importance of predictive biomarkers in MET-targeted cancer therapy.
Main Methods:
- Review of current MET-targeted therapies and their associated diagnostic assays.
- Analysis of genetic alterations in MET, including exon 14 skipping and amplification.
- Evaluation of fluorescence in situ hybridization (FISH) for detecting MET amplification (MET/CEP7 ratio).
Main Results:
- Capmatinib is the only approved MET-targeted drug with a CDx assay for NSCLC with MET exon 14 skipping.
- MET amplification is a resistance mechanism in EGFR-mutated NSCLC.
- The MET/CEP7 ratio detected by FISH shows strong predictive properties for MET amplification, excluding polysomy.
Conclusions:
- Companion diagnostic assays are essential for the effective use of MET-targeted therapies in NSCLC.
- Accurate identification of MET alterations, such as exon 14 skipping and amplification, guides treatment decisions.
- Further development and validation of predictive biomarkers are critical for advancing MET-targeted cancer treatment.
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