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

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

doi:10.1038/s41467-023-35961-y

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

188 Scopus citations

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.

Original language	English
Article number	1070
Pages (from-to)	1070
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-35961-y
State	Published - 27 02 2023
Externally published	Yes

Bibliographical note

Keywords

Humans
Carcinoma, Non-Small-Cell Lung/drug therapy
ErbB Receptors/genetics
Lung Neoplasms/drug therapy
Mutation
Protein Kinase Inhibitors/pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-023-35961-y

Cite this

Chmielecki, J., Gray, J. E., Cheng, Y., Ohe, Y., Imamura, F., Cho, B. C., Lin, M. C., Majem, M., Shah, R., Rukazenkov, Y., Todd, A., Markovets, A., Barrett, J. C., Hartmaier, R. J., & Ramalingam, S. S. (2023). Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nature Communications, 14(1), 1070. Article 1070. https://doi.org/10.1038/s41467-023-35961-y

@article{779580570e874872bbe7555fcb8bf9be,

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

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.",

keywords = "Humans, Carcinoma, Non-Small-Cell Lung/drug therapy, ErbB Receptors/genetics, Lung Neoplasms/drug therapy, Mutation, Protein Kinase Inhibitors/pharmacology",

author = "Juliann Chmielecki and Gray, \{Jhanelle E.\} and Ying Cheng and Yuichiro Ohe and Fumio Imamura and Cho, \{Byoung Chul\} and Lin, \{Meng Chih\} and Margarita Majem and Riyaz Shah and Yuri Rukazenkov and Alexander Todd and Aleksandra Markovets and Barrett, \{J. Carl\} and Hartmaier, \{Ryan J.\} and Ramalingam, \{Suresh S.\}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = feb,

day = "27",

doi = "10.1038/s41467-023-35961-y",

language = "英语",

volume = "14",

pages = "1070",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Chmielecki, J, Gray, JE, Cheng, Y, Ohe, Y, Imamura, F, Cho, BC, Lin, MC, Majem, M, Shah, R, Rukazenkov, Y, Todd, A, Markovets, A, Barrett, JC, Hartmaier, RJ & Ramalingam, SS 2023, 'Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer', Nature Communications, vol. 14, no. 1, 1070, pp. 1070. https://doi.org/10.1038/s41467-023-35961-y

TY - JOUR

T1 - Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer

AU - Chmielecki, Juliann

AU - Gray, Jhanelle E.

AU - Cheng, Ying

AU - Ohe, Yuichiro

AU - Imamura, Fumio

AU - Cho, Byoung Chul

AU - Lin, Meng Chih

AU - Majem, Margarita

AU - Shah, Riyaz

AU - Rukazenkov, Yuri

AU - Todd, Alexander

AU - Markovets, Aleksandra

AU - Barrett, J. Carl

AU - Hartmaier, Ryan J.

AU - Ramalingam, Suresh S.

PY - 2023/2/27

Y1 - 2023/2/27

N2 - 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.

AB - 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.

KW - Humans

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - ErbB Receptors/genetics

KW - Lung Neoplasms/drug therapy

KW - Mutation

KW - Protein Kinase Inhibitors/pharmacology

UR - https://www.scopus.com/pages/publications/85148967239

U2 - 10.1038/s41467-023-35961-y

DO - 10.1038/s41467-023-35961-y

M3 - 文章

C2 - 36849494

AN - SCOPUS:85148967239

SN - 2041-1723

VL - 14

SP - 1070

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1070

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this