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

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: 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 447 Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120, to YL WU). Medical writing support was provided by Siân Marshall PhD, SIANTIFIX Inc., Cambridge, UK, funded by ACEA Therapeutics Inc. 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. Ethical Approval: 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.