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The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer

38 Pages Posted: 1 Mar 2019

See all articles by Yi-Chen Zhang

Yi-Chen Zhang

Guangdong Academy of Medical Sciences

Zhi-Hong Chen

Guangdong Academy of Medical Sciences

Xu-Chao Zhang

Guangdong Academy of Medical Sciences

Chong-Rui Xu

Guangdong Academy of Medical Sciences

Hong-Hong Yan

Guangdong Academy of Medical Sciences

Zhi Xie

Guangdong Academy of Medical Sciences

Shao-Kun Chuai

Burning Rock Biotech

Jun-Yi Ye

Burning Rock Biotech

Han Zhang-Han

Burning Rock Biotech

Zhou Zhang

Burning Rock Biotech

Xiao-Yan Bai

Guangdong Academy of Medical Sciences

Jian Su

Guangdong Academy of Medical Sciences

Bin Gan

Guangdong Academy of Medical Sciences

Jin-Ji Yang

Guangdong Academy of Medical Sciences

Wen-Feng Li

Guangdong Academy of Medical Sciences

Wei Tang

ACEA Therapeutics Inc.

Feng Roger Luo

ACEA Therapeutics Inc.

Xiao Xu

ACEA Therapeutics Inc.

Yi-Long Wu

Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Lung Cancer Institute, Department of Pulmonary Oncology

Qing Zhou

Guangdong Academy of Medical Sciences

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Multiple version iconThere are 2 versions of this paper

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), and describe clinical strategies to overcome EGFR amplification-mediated resistance.  

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-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis.  

Findings: Thirty-two of 73 patients enrolled were eligible for resistance analysis. A heterogeneous landscape of resistance mechanisms to abivertinib was observed with 14% (4/28) experiencing EGFR T790M loss and 13% (4/32) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (34%), and considered a putative resistance mechanism in seven (22%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. We demonstrated that abivertinib plus nimotuzumab or afatinib is effective and tolerable in overcoming EGFR amplification-mediated resistance to abivertinib.  

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 and may be overcome by combining abivertinib with an EGFR monoclonal antibody or afatinib.   

Funding Statement: 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).

Declaration of Interest: QZ declares grants from National Key R&D Program of China, speaker fees from AstraZeneca and Roche. Y-LW declares grants from Key Lab System Project of Guangdong Science and Technology Department, 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, H-ZH, ZZ are employees of Burning Rock Biotech. Other authors declare no competing interests.

Ethics Approval Statement: This study was approved by the ethics committee at Guangdong General Hospital, and all patients provided written, informed consent. The study adhered to the principles of Declaration of Helsinki and the Good Clinical Practice guidelines.

Keywords: EGFR; T790M; abivertinib; resistance; NSCLC

Suggested Citation

Zhang, Yi-Chen and Chen, Zhi-Hong and Zhang, Xu-Chao and Xu, Chong-Rui and Yan, Hong-Hong and Xie, Zhi and Chuai, Shao-Kun and Ye, Jun-Yi and Zhang-Han, Han and Zhang, Zhou and Bai, Xiao-Yan and Su, Jian and Gan, Bin and Yang, Jin-Ji and Li, Wen-Feng and Tang, Wei and Luo, Feng Roger and Xu, Xiao and Wu, Yi-Long and Zhou, Qing, The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer (02/21/2019 09:38:49). Available at SSRN: https://ssrn.com/abstract=3341474

Yi-Chen Zhang

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Zhi-Hong Chen

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Xu-Chao Zhang

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Chong-Rui Xu

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Hong-Hong Yan

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Zhi Xie

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Shao-Kun Chuai

Burning Rock Biotech

Guangzhou
China

Jun-Yi Ye

Burning Rock Biotech

Guangzhou
China

Han Zhang-Han

Burning Rock Biotech

Guangzhou
China

Zhou Zhang

Burning Rock Biotech

Guangzhou
China

Xiao-Yan Bai

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Jian Su

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Bin Gan

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Jin-Ji Yang

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Wen-Feng Li

Guangdong Academy of Medical Sciences

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Wei Tang

ACEA Therapeutics Inc.

San Diego, CA
United States

Feng Roger Luo

ACEA Therapeutics Inc.

San Diego, CA
United States

Xiao Xu

ACEA Therapeutics Inc.

San Diego, CA
United States

Yi-Long Wu (Contact Author)

Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Lung Cancer Institute, Department of Pulmonary Oncology ( email )

China

Qing Zhou

Guangdong Academy of Medical Sciences ( email )

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

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