Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET Exon 14 splicing alternations.

Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to crizotinib in human lung adenocarcinomas. However, a substantial part of patients still has no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations. Here we described the MET exon 14 splicing mutations in cell-free circulating-tumor DNA by next-generation sequencing (NGS) technology. Patient firstly responded to crizotinib therapy within four months, however, three acquired mutation in the MET kinase domain, D1228N/H and Y1230H, were found at the time of disease progression. To our knowledge, this is the first clinical report of three mutations simultaneously arising in a patient with MET exon 14 splicing mutation.