Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping.

UNLABELLED: MET exon 14 skipping alterations ( MET ex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in MET ex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described.

MATERIALS AND METHODS: MET ex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and MET ex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to MET ex14 were evaluated.

RESULTS: Of 40,824 NSCLCs, 692 MET ex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with MET ex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, MET ex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to MET ex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance.

CONCLUSION: MET ex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether MET ex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.