Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort

Published on 2019-10-11T05:39:03Z (GMT) by
Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.

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Fairclough, Stephen; Kiedrowski, Lesli; Lin, Jessica; Zelichov, Ori; Tarcic, Gabi; Stinchcombe, Thomas; et al. (2019): Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4694918.v1