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

Yi Chen Zhang, Zhi Hong Chen, Xu Chao Zhang, Chong Rui Xu, Hong Hong Yan, Zhi Xie, Shao Kun Chuai, Jun Yi Ye, Han Han-Zhang, Zhou Zhang, Xiao Yan Bai, Jian Su, Bin Gan, Jin Ji Yang, Wen Feng Li, Wei Tang, Feng Roger Luo, Xiao Xu, Yi Long Wu*, Qing Zhou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)180-187
Number of pages8
JournalEBioMedicine
Volume43
DOIs
StatePublished - May 2019
Externally publishedYes

Keywords

  • Abivertinib
  • EGFR T790M mutation
  • EGFR amplification
  • NSCLC
  • Resistance mechanisms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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