Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 27;14(1):1071.
doi: 10.1038/s41467-023-35962-x.

Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial

Juliann Chmielecki  1 , Tony Mok  2 , Yi-Long Wu  3 , Ji-Youn Han  4 , Myung-Ju Ahn  5 , Suresh S Ramalingam  6 , Thomas John  7 , Isamu Okamoto  8 , James Chih-Hsin Yang  9 , Frances A Shepherd  10 , Krishna C Bulusu  11 , Gianluca Laus  11   12 , Barbara Collins  13   14 , J Carl Barrett  1 , Ryan J Hartmaier  1 , Vassiliki Papadimitrakopoulou  15   16
Affiliations

Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial

Juliann Chmielecki et al. Nat Commun. .

Abstract

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing interests: J.C. reports employment and stock ownership with AstraZeneca. T.M. reports employment with The Chinese University of Hong Kong; reports stock ownership with Aurora Tele-Oncology Ltd., Hutchison Chi-Med, and Sanomics Ltd.; has undertaken an advisory role for AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb Company, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics, Inc.,Gritstone Oncology, Inc., Guardant Health, geneDecode Co., Ltd., Hengrui Therapeutics Inc., Hutchison Chi-Med, Ignyta, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lily, Loxo-Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech,Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; is on the board of directors for AstraZeneca and Hutchison Chi-Med; has received honoraria from Abbvie Inc., ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., LTD., AstraZeneca, BeiGene, Berry Oncology, BI, Blueprint Medicines Corporation, BMS, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., Ignyta, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lilly, Loxo-Oncology, Lunit, Inc., Merck Serono, MSD, Mirati Therapeutics Inc., MoreHealth, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Roche Pharmaceuticals, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Takeda Pharmaceuticals HK Ltd., Vertex Pharmaceuticals, and Yuhan Corporation; has received consulting fees from AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb Company, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics, Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., Hutchison Chi-Med, Ignyta, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lily, Loxo-Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; and has received grants or funds from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery. Y.-L.W. reports institutional funding from AstraZeneca, Bristol-Myers Squibb, Pfizer, and Roche; and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Sanofi, and Roche. J-Y.H. has undertaken an advisory role for Novartis, MSD Oncology, AstraZeneca, Lilly, and Takeda; has received honoraria from Roche, AstraZeneca, and Takeda; and has received grants or funds from Roche, Pfizer, and ONO. M.-J.A. has undertaken an advisory role for AstraZeneca, Bristol-Myers Squibb, MSD, ONO Pharmaceutical, Roche, Takeda, and Alpha Pharmaceutical; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, ONO Pharmaceutical, and Roche. S.S.R. has undertaken an advisory role for Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Tesaro, Takeda, GlaxoSmithkline, Daichii Sankyo, and Eisai; has received consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Tesaro, Takeda, Glaxo smithkline, Daichii Sankyo, and Eisai; and has received grants or funds from Amgen, Advaxis, AstraZeneca, BMS, Merck, Tesaro, Takeda, and Genmab. T.J. has undertaken an advisory role for, and received consulting fees from, Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZenca, Takeda, MSD, Specialized Therapeutics, and Pfizer. I.O. has undertaken an advisory role for AstraZeneca and Chugai Pharma AbbVie; has received honoraria from AstraZeneca, Taiho Pharmaceutical, ONO Pharmaceutical, MSD Oncology, Bristol-Myers Squibb, Chugai Pharma, and Pfizer; and has received grants or funds from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, ONO Pharmaceutical, MSD Oncology, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, and AbbVie. J.C-H.Y. reports employment with the National Taiwan University Cancer Center; has undertaken an advisory role for Bayer, Roche/Genentech, AstraZeneca, MSD, Merck Serono, Pfizer, Novartis, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Jannsen, Boehringer Ingelheim, GSK, and IPSEN; is on the board of directors for the International Association for the Study of Lung Cancer; has received honoraria from Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, ONO Pharmaceuticals, and Boehringer Ingelheim; and has received consulting fees from Bayer, Roche/Genentech, Chugai, AstraZeneca, MSD, Merck Serono, Pfizer, Novartis, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, and Boehringer Ingelheim. F.A.S. reports stock ownership with AstraZeneca. K.C.B. reports employment and stock ownership with AstraZeneca. G.L. reports employment and stock ownership with AstraZeneca. B.C. is a contactor for AstraZeneca. J.C.B. reports employment and stock ownership with AstraZeneca. R.J.H. reports employment and stock ownership with AstraZeneca. V.P. has undertaken a scientific advisory role for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, AbbVie, Araxes, Arrys Therapeutics, Bolt Therapeutics, Clovis Oncology, Exelixis, G2 Innovation, Gritstone, Ideaya, Leeds Biolabs, Loxo-Oncology, Takeda, Tesaro, and TRM Oncology; has received honoraria from F. Hoffman-La Roche; and has received research funding from AstraZeneca, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers-Squibb, Checkmate, and Incyte.

Figures

Fig. 1
Fig. 1. Patient disposition.
CONSORT flow diagram of patient disposition and eligibility in the analysis of mechanisms of acquired resistance in the AURA3 trial. *Plasma provided at baseline and at disease progression or treatment discontinuation. EGFR epidermal growth factor receptor, p.o, orally, qd once daily, TKI tyrosine kinase inhibitor.
Fig. 2
Fig. 2. Acquired alterations in osimertinib-treated patients and in chemotherapy-treated patients.
Tile plots indicating A acquired alterations in osimertinib-treated patients (n = 78) and B acquired alterations in chemotherapy-treated patients (n = 25) from the AURA3 trial. Source data are provided in the Supplementary Data 1 file. *C797S or C797G; †L792F or L792H. EGFR epidermal growth factor receptor.
Fig. 3
Fig. 3. Osimertinib duration of treatment by candidate mechanism and T790M status.
Swimmer plot indicating the duration of treatment with osimertinib (months) by candidate mechanism and T790M status (n = 78). Source data are provided in the Supplementary Data 1 file. X time of death for patients who have died, O date last known alive for patients who have not died, D time of study discontinuation.
See this image and copyright information in PMC

References

    1. Planchard, D. et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. ESMO Guidelines CommitteeUpdated version published 15 Septemberhttps://www.esmo.org/guidelines/lung-and-chest-tumours/clinical-practice... (2020).
    1. Oxnard GR, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin. Cancer Res. 2011;17:1616–1622. doi: 10.1158/1078-0432.CCR-10-2692. - DOI - PMC - PubMed
    1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 2013;19:2240–2247. doi: 10.1158/1078-0432.CCR-12-2246. - DOI - PMC - PubMed
    1. Jänne PA, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2014;15:1433–1441. doi: 10.1016/S1470-2045(14)70461-9. - DOI - PubMed
    1. Wu SG, et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016;7:12404–12413. doi: 10.18632/oncotarget.7189. - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources