Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer.

backgroundMET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC) and can emerge as an acquired drug resistance mechanism to MET, EGFR or ALK inhibitors. The clinical and genomic features of METΔex14 in NSCLC require further characterization.

methodsOur study included a total of 585 patients with METΔex14 + NSCLC, comprising 556 baseline samples, 53 samples from patients exhibiting resistance to MET inhibitors, and 16 samples from patients resistant to EGFR/ALK inhibitors. Genomic data from targeted next-generation sequencing (NGS) of tissue and/or plasma samples using GeneseeqPrime™ (a 425 pan-cancer gene panel) were analyzed.

resultsOverall, METΔex14 exhibited a prevalence of 1.02% (n = 585) in the screened NSCLC population, with a higher incidence in patients with a sarcomatoid histology. METΔex14 was predominantly detected at the splice donor site, though the non-coding region adjacent to the splice acceptor site contributed considerably to the complexity of METΔex14. Common concurrent alterations identified at baseline included those in TP53 (40.8%), CDK4 (16%) and EGFR (12.4%). Concurrent MET amplification and cell cycle pathway mutations were both associated with worse outcomes in patients treated with crizotinib, with significant co-occurrences observed also among these concurrent genomic variations. In addition, increased chromosomal instability and intra-tumoral heterogeneity correlated with a poorer response to crizotinib. Mechanisms of acquired resistance to MET inhibitors were primarily attributed to on-target MET D1228X/Y1230X mutations or off-target alterations within genes in the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways. Intriguingly, our exploratory analysis also identified the FGFR3::TACC3 fusion as a potential resistance mechanism to savolitinib. Moreover, METΔex14 was identified in 16 patients following progression on EGFR and ALK inhibitors, highlighting the need for developing tailored therapeutic strategies to overcome resistance.

conclusionsThis study provides a comprehensive characterization of METΔex14 in NSCLC, revealing its dual role as a primary driver of oncogenesis and a potential resistance mechanism to EGFR/ALK inhibitors. The identification of concurrent genetic alterations and potential resistance mechanisms enhances our molecular understanding of treatment responses. These findings highlight the need for further investigation into targeted therapies that consider the genomic complexity of METΔex14 to improve treatment efficacy and patient outcomes.