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

被引：132

作者：

Chmielecki, Juliann ^{[1
]}

Gray, Jhanelle E. ^{[2
]}

Cheng, Ying ^{[3
]}

Ohe, Yuichiro ^{[4
]}

Imamura, Fumio ^{[5
]}

Cho, Byoung Chul ^{[6
]}

Lin, Meng-Chih ^{[7
]}

Majem, Margarita ^{[8
]}

Shah, Riyaz ^{[9
]}

Rukazenkov, Yuri ^{[10
]}

Todd, Alexander ^{[11
]}

Markovets, Aleksandra ^{[1
]}

Barrett, J. Carl ^{[1
]}

Hartmaier, Ryan J. ^{[1
]}

Ramalingam, Suresh S. ^{[12
]}

机构：

[1] AstraZeneca, Translat Med, Oncol R&D, Boston, MA USA

[2] H Lee Moffitt Canc Ctr & Res Inst, Dept Thorac Oncol, Tampa, FL 33612 USA

[3] Jilin Prov Canc Hosp, Changchun, Peoples R China

[4] Natl Canc Ctr, Dept Thorac Oncol, Tokyo, Japan

[5] Osaka Int Canc Inst, Dept Thorac Oncol, Osaka, Japan

[6] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Div Med Oncol,Dept Internal Med, Seoul, South Korea

[7] Chang Gung Univ, Kaohsiung Chang Gung Mem Hosp, Div Pulm & Crit Care Med, Kaohsiung, Taiwan

[8] Hosp Santa Creu & Sant Pau, Med Oncol Dept, Barcelona, Spain

[9] Maidstone Hlth Author, Kent Oncol Ctr, Maidstone & Tunbridge Wells NHS Trust, Maidstone, England

[10] AstraZeneca, Oncol R&D, Cambridge, England

[11] AstraZeneca, Oncol R&D, Oncol Biometr, Cambridge, England

[12] Emory Univ, Winship Canc Inst, Atlanta, GA USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

AZD9291; INHIBITORS; TKI; ADENOCARCINOMA; AFATINIB; OUTCOMES; T790M;

D O I：

10.1038/s41467-023-35961-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial. 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.

引用

页数：9

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