EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation that displays sensitivity to approved and in-development lung cancer EGFR tyrosine kinase inhibitors

Abstract Background The epidermal growth factor receptor (EGFR)-A763_Y764insFQEA is a unique exon 20 insertion mutation (∼5-6% of exon 20 insertions) that at the structural and enzyme kinetic level more closely resembles EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants such as EGFR-exon 19 indels and L858R. A limited number of preclinical models and clinical reports have studied the response of this mutant to EGFR TKIs. Methods We use models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative 1st (gefitinib, erlotinib), 2nd (afatinib), 3rd generation (osimertinib), and in-development EGFR exon 20-specific (poziotinib, mobocertinib [TAK-788]) TKIs. We also compile outcomes of EGFR-A763_Y764insFQEA mutated lung cancers treated with EGFR TKIs. Results Cells driven by EGFR-A763_Y764insFQEA are consistently sensitive to EGFR TKIs—as opposed to those driven by typical EGFR exon 20 insertions (A767_V769dupASV, D770_N771insSVD and H773_V774insH), which only are inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. The majority (62.5% [95%CI:39-86%], n=16) of patients with lung cancers harboring EGFR-A763_Y764insFQEA respond to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib), and with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI-treated cases is 22 months (95%CI:16-25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but seem to align with those of common mutations. Conclusions This is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available 1st, 2nd, and 3rd generation as well as in-development EGFR TKIs.