Introduction: The EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation (~5% to 6% of exon 20 insertions), which, 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 used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first- (gefitinib, erlotinib), second- (afatinib), third-generation (osimertinib), and in-development EGFR exon 20-specific (poziotinib, mobocertinib [TAK-788]) TKIs. We also compiled outcomes of EGFR-A763_Y764insFQEA-mutated lung cancers treated with EGFR TKIs.
Results: Cells driven by EGFR-A763_Y764insFQEA were consistently sensitive to EGFR TKIs (as opposed to those driven by typical EGFR exon 20 insertions [A767_V769dupASV, D770_N771insSVD and H773_V774insH]), which were only inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. Most case instances (62.5% [95% confidence interval: 39%-86%], n = 16) with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib) with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI-treated cases was 22 months (95% confidence interval: 16-25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations.
Conclusions: To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available first-, second-, third-generation, and in-development EGFR TKIs.
Keywords: A763_Y764insFQEA; EGFR exon 20 insertion; Kinase inhibitor; Lung cancer; Mobocertinib; Osimertinib.