Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).

9069 Background: Non-small cell lung cancers (NSCLC) harboring METex14 activating mutations can respond dramatically to treatment with MET TKIs, but the mechanisms of acquired resistance to these therapies are not well understood. Methods: We performed next generation sequencing on serial plasma samples and/or tumor biopsies and one autopsy case from patients with METex14 mutant NSCLC to identify mechanisms of resistance to the type 1 MET TKI crizotinib and the type 2 MET TKI glesatinib. Results: Samples from 12 patients with METex14 mutant NSCLC were included in this analysis. In 4 cases (33%), acquired MET alterations were identified including one case with amplification of the mutated METex14 allele and three cases with MET tyrosine kinase domain secondary site mutations; in two of these cases, more than one MET resistance mutation was present in the same patient. Secondary mutations in MET included H1094Y, G1163R, L1195F, L1195V, D1228N, Y1230H, and Y1230S. In 4 cases (33%), bypass track activation was identified, including massive genomic amplification of wild-type KRAS, BRAF, and/or EGFR. In 4 cases (33%), the resistance mechanism was not identifiable. A case of acquired resistance to glesatinib with acquired amplification of the mutated METex14 allele had a confirmed partial response after switching to crizotinib. Data from resistant preclinical models and patient-derived cell lines and mouse xenografts will be presented. Conclusions: Novel therapeutic strategies will be needed to delay or overcome multiple complex mechanisms of acquired MET TKI resistance in METex14 mutant NSCLC.