Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer

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Authors: Juliann Chmielecki ; Jhanelle E Gray ; Ying Cheng ; Yuichiro Ohe ; Fumio Imamura ; Byoung Chul Cho ; Meng-Chih Lin ; Margarita Majem ; Riyaz Shah ; Yuri Rukazenkov ; Alexander Todd ; Aleksandra Markovets ; J Carl Barrett ; Ryan J Hartmaier ; Suresh S Ramalingam

MeSH: Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; ErbB Receptors / genetics ; Humans ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Mutation ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use

Abstract: Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted. © 2023. The Author(s).