@article{2f2705f8cbfa4144919ab3aaf8832bde,
title = "Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial",
abstract = "Background: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367). Methods: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50–350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing (NGS)-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. Findings: Thirty of 73 patients enrolled were eligible for resistance analysis. Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and three patients only provided tissue samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed: 15% (4/27) experienced EGFR T790M loss and 13% (4/30) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (37%), and considered a putative resistance mechanism in seven (23%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. Interpretation: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort. Fund: The National Key R&D Program of China (Grant No. 2016YFC1303800), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120).",
keywords = "Abivertinib, EGFR T790M mutation, EGFR amplification, NSCLC, Resistance mechanisms",
author = "Zhang, {Yi Chen} and Chen, {Zhi Hong} and Zhang, {Xu Chao} and Xu, {Chong Rui} and Yan, {Hong Hong} and Zhi Xie and Chuai, {Shao Kun} and Ye, {Jun Yi} and Han Han-Zhang and Zhou Zhang and Bai, {Xiao Yan} and Jian Su and Bin Gan and Yang, {Jin Ji} and Li, {Wen Feng} and Wei Tang and Luo, {Feng Roger} and Xiao Xu and Wu, {Yi Long} and Qing Zhou",
note = "Funding Information: The authors thank the patients, their families and the study personnel who participated in this trial. This work was supported by The National Key R&D Program of China (Grant No. 2016YFC1303800 , to Q Zhou), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006 / 2017B030314120 , to YL WU). Funding Information: The authors thank the patients, their families and the study personnel who participated in this trial. This work was supported by The National Key R&D Program of China (Grant No. 2016YFC1303800, to Q Zhou), Key Lab System Project of Guangdong Science and Technology Department ? Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120, to YL WU). Medical writing support was provided by Si?n Marshall PhD, SIANTIFIX Inc. Cambridge, UK, funded by ACEA Therapeutics Inc. The authors thank Dr. Ming-Feng Zhang and Dr. Qing Gou for contribution to clinical data collection. The funder of this study had no role in study design, data collection, data analysis, and data interpretation. This manuscript was written by the authors with medical writing support funded by ACEA Therapeutics Inc. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. QZ declares speaker fees from AstraZeneca and Roche. Y-LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. XX is the CEO and stock owner of ACEA Therapeutics Inc. WT, FRL are employees of ACEA Therapeutics Inc. S-KC, J-YY, HH-Z, ZZ are employees of Burning Rock Biotech. Other authors declare no competing interests. Y-LW and QZ designed the study. QZ and Y-CZ perform the literature search. QZ, Y-CZ, Z-HC and BG contributed to clinical samples collection. S-KC, J-YY, HH-Z and ZZ performed the genomic analysis. Y-CZ, Z-HC, J-YY and H-HY were involved in data interpretation and statistical analysis. J-YY and W-FL were involved in figure editing. ZX and Y-CZ performed the FISH analyses. Y-CZ, QZ and Y-LW developed the initial draft of the manuscript. Y-LW, QZ, X-CZ, WT, RFL, XX contributed to critically review the initial draft of the manuscript. Y-CZ, QZ, Y-LW, X-CZ, C-RX, X-YB, JS, J-JY involved in producing the subsequent drafts of the manuscript and finalization of the report. Funding Information: Medical writing support was provided by Si{\^a}n Marshall PhD, SIANTIFIX Inc., Cambridge, UK, funded by ACEA Therapeutics Inc. The authors thank Dr. Ming-Feng Zhang and Dr. Qing Gou for contribution to clinical data collection. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = may,
doi = "10.1016/j.ebiom.2019.04.030",
language = "English (US)",
volume = "43",
pages = "180--187",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}
