EGFR-A763_Y764insFQEA: A unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.

Abstract

e20593 Background: The epidermal growth factor receptor (EGFR)-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation (accounting for ~10-20% of all EGFR exon 20 insertions) that more closely resembles EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants (i.e. EGFR-exon 19 deletions and L858R) at the structural and enzymatic level as compared to other non-classical mutations. A limited number of preclinical models and clinical reports have detailed the response of EGFR-A763_Y764insFQEA-driven lung tumors to approved or in-development TKIs. Methods: Multiple preclinical models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations were used to probe representative 1st generation (gefitinib, erlotinib), 2nd generation (afatinib, dacomitinib), 3rd generation (osimertinib), and in-development EGFR exon 20 specific (poziotinib, others) TKIs. Clinical outcomes and prior reports of EGFR-A763_Y764insFQEA mutated lung adenocarcinomas treated with EGFR TKIs were compiled. Results: Cell lines driven by EGFR-A763_Y764insFQEA were consistently sensitive to 1st, 2nd and 3rd generation EGFR TKIs, while models driven by other EGFR exon 20 insertions (i.e. D770_N771insSVD and H773_V774insH) were only inhibited by in-development EGFR TKIs and at doses below those affecting the wild-type receptor. The majority of patients with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinical doses of 1st, 2nd, and 3rd generation EGFR TKIs; and lung cancers with these mutants are currently enrolled in clinical trials of in-development EGFR exon 20 specific TKIs. Conclusions: This is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation sensitive to 1st, 2nd, 3rd generation and in-development EGFR exon 20 specific TKIs. Mechanisms of acquired resistance of this mutant to different EGFR TKIs remain unreported.