Detection ofMETexon 14 skipping mutations in non-small cell lung cancer: overview and community perspective

Abstract

Introduction: Non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancer diagnoses in the United States, has many known driver mutations, including MET exon 14 skipping mutation (METex14). The detection of oncogenic driver mutations in NSCLC and the development of drugs to target these alterations, including METex14, has created the need for accurate and reliable testing, of which next-generation sequencing (NGS) is the gold standard. However, detection of METex14 in patients with NSCLC can be challenging due to the complex biology of METex14 and the abilities of different NGS platforms to detect METex14. Areas covered: This review provides an overview of METex14 biology, discusses the optimal platforms for the detection of METex14 in NSCLC, and provides an overview of the use of NGS in the community setting. Expert opinion: Broad molecular testing is crucial for identifying actionable oncogenic drivers in NSCLC. METex14 is a complex oncogenic driver mutation requiring carefully optimized platforms for proper detection. To identify patients eligible for targeted therapies -including therapies targeting novel oncogenic drivers, such as MET inhibitors -community oncologists need to be aware of both the use of NGS platforms and the differences in their capabilities to detect certain oncogenic drivers.

Robust Performance of the Novel Research-Use-Only Idylla GeneFusion Assay Using a Diverse Set of Pathological Samples with a Proposed 1-Day Workflow for Advanced NSCLC Evaluation

“…A subsequent analysis with a second RT-PCR assay, EasyPGX ® , was in agreement with Idylla, raising the suspicion of an NGS false positive result. An alert has recently been reported showing that false MET ex14 skipping might be caused by the homopolymeric error of the splice donor site with the Oncomine Dx Target test [20,21]. These false positives could be distinguished by relatively low read counts.…”

Consensus Recommendations to Optimize Testing for New Targetable Alterations in Non-Small Cell Lung Cancer

“…Panel selection based on target enrichment approaches has been demonstrated to be critical when detecting alterations such as MET exon 14 skipping ( MET ex14) events, as an example. Due to the diversity of mechanisms that can lead to MET ex14 events, utilizing an amplicon-based NGS panel results in reduced detection rates due to the diversity of alterations, and thus hybrid-capture has been the preferred approach when performing DNA-only-based testing [ 50 , 51 ]. Parallel or sequential RNA-based testing can aid in identifying MET ex14 events by detecting fusions of exons 13 and 15.…”

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

“…With an increasing number of MET TKIs approved for marketing, selecting a suitable agent for patients has become an urgent need for clinicians. Currently, the approved MET TKIs include crizotinib, savolitinib, capmatinib, and tepotinib 12 . From the perspective of accessibility, the available MET TKIs in China cover crizotinib and savolitinib.…”

“…Currently, the approved MET TKIs include crizotinib, savolitinib, capmatinib, and tepotinib. 12 From the perspective of accessibility, the available MET TKIs in China cover crizotinib and savolitinib. Hence, our study cross‐sectionally compared the efficacy between crizotinib and savolitinib in NSCLC patients with METex14 skipping and MET amplification.…”