Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations

Background The hepatocyte growth factor receptor gene ( MET ) exon 14 skipping ( METex14 ) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods Well-validated hybrid capture–based comprehensive genomic profiling was performed at the request of individual treating physicians. Results Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14 , including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43–95) and 60% were female. Concurrent, murine double minute gene ( MDM2 ) amplification, cyclin-dependent kinase 4 gene ( CDK4 ) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14 , respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification ( MET amp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the MET amp and non- MET amp samples. Response to MET TKI was observed in both in patients with MET amp and in patients without MET amp METex14 . Conclusion Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture–based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.