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

• Type of Material: Article
• Authors: Juliann Chmielecki, AstraZeneca; Jhanelle E. Gray, H Lee Moffitt Cancer Centre & Research Institute; Ying Cheng, Jilin Provincial Cancer Hospital; Yuichiro Ohe, National Cancer Center Hospital; Fumio Imamura, Osaka International Cancer Institute; Byoung Chul Cho, Yonsei University; Meng-Chih Lin, Chang Gung University; Margarita Majem, Hospital de la Santa Creu i Sant Pau; Riyaz Shah, Maidstone Health Author; Yuri Rukazenkov, AstraZeneca; Alexander Todd, AstraZeneca; Aleksandra Markovets, AstraZeneca; J. Carl Barrett, AstraZeneca; Ryan J. Hartmaier, AstraZeneca; Suresh Ramalingam, Emory University
• Language: English
• Date: 2023-02-27
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023, corrected publication 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-35961-y
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 1070
• End Page: 1070
• Keywords: Science & Technology - Other Topics; ADENOCARCINOMA; Multidisciplinary Sciences; OUTCOMES; TKI; AFATINIB; AZD9291; INHIBITORS; Science & Technology; T790M
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.