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

Abstract

<i>MET</i> exon 14 skipping alterations (<i>MET</i>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 <i>MET</i>ex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. <i>MET</i>ex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and <i>MET</i>ex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to <i>MET</i>ex14 were evaluated. Of 40,824 NSCLCs, 692 <i>MET</i>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. <i>MET</i> 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 <i>MET</i> co-occurs in 5%-6%. When co-occurring with <i>MET</i>ex14, <i>EGFR</i> mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, <i>MET</i>ex14 (39%, 7 of 18) and <i>KRAS</i> (44%, 8 of 18) had similar rates of clonal dominance. <i>PIK3CA and PTEN</i> mutations were almost always subclones (89%, 16 of 18) to <i>MET</i>ex14. Moreover, <i>RET-CCDC6</i> fusion and <i>EGFR</i> mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. <i>MET</i>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 <i>MET</i>ex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.