Table 1.

EGFR-mutations associated with reduced response or primary resistance to EGFR-TKIs in NSCLC.

Somatic Mutation (Amino Acid Position)	Exon	Effect on EGFR-TKIs	Other Features	References
G719X S768I L861Q	18 20 21	Reduced response to 1G TKIs in pts. & preclinical models. Sensitive to afatinib. Osimertinib less effective in pts. or cell lines with these mutants than in those with classic EGFR-mutants, regardless of presence of T790M co-mutation.	Significantly less sensitive than L858R & exon 19dels but do show some response to 1G TKIs. Can co-occur together or with sensitizing mutations, especially L858R. The rare variant L861P reported co-existing with L858R in pts. not responding to 1G EGFR-TKIs.	[54,76,81,83,87,89,90,92,94]
L747P	19	Intrinsic resistance to EGFR-TKIs of all three generations	Very rare, resistance mechanism unclear. The variant L747S occasionally reported both as secondary TKI-resistant mutant in the setting of acquired TKI-resistance and as de novo mutation in cases with co-existing L858R not responding to 1G EGFR-TKIs.	[54,57,58,86,99,101]
Exon 19 insertions	19	Unclear (very rare, require further investigations)	Some epidemiological evidence for lower TKI-sensitivity than common EGFR-mutations.	[51,97,98]
Exon 20 insertions	20	Poor response to 1G/2G TKIs; in vitro appear responsive to osimertinib & single cases were reported sensitive to osimertinib.	A763_Y764insFQEA is an exception, as structurally resembles L858R & is sensitive to TKIs. In preclinical models, exon 20ins responded to cetuximab + afatinib or osimertinib. Cases responding to afatinib + cetuximab have been reported. Promising results in vitro and in vivo from new selective TKIs targeting EGFR and ERBB2 exon 20 insertions, such as poziotinib, TAS6417, and TAK-788. Heat shock protein 90 inhibitors also potentially active against NSCLC cells with EGFR exon 20ins.	[83,86,87,103,104,106,108,110,112]
T790M	20	Resistant to 1G/2G TKIs, sensitive to 3G TKIs.	Present as de novo mutation, either alone or with a common sensitizing mutation such as L858R. Amplification of T790M-positive EGFR may provide further TKI-resistance. High relative abundance of T790M predicts poor response to 1G/2G TKIs but may predict better response to 3G TKIs.	[51,54,57,61,62]
Germline T790M	20	Resistant to 1G/2G TKIs, sensitive to 3G TKIs.	Predominantly in females, non-smokers with a secondary somatic EGFR-mutation.	[115]
Germline V843I	21	Resistant to 1G/2G TKIs, possibly sensitive to 3G TKIs.	As T790M sterically hinders TKI-binding to EGFR.	[113,114,115]