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Table 3 Mechanisms of resistance to third generation EGFR TKIs

From: Third generation EGFR TKIs: current data and future directions

Mechanism Author 3rd gen EGFR TKI Sample Method Other mechanisms (no. of patients)
EGFR-dependent mechanisms of resistance to third generation TKIs
C797S Thress et al.
Yu et al.
Ortiz Cuaran
Ramalingam
Ig Ou
Ou ASCO
Piotrowska WCLC
Osimertinib Plasma/Tissue
Tissue
Tissue
Plasma
Plasma
Plasma/Tissue
Plasma
NGS,ddPCR
NGS
NGS
NGS
NGS
NGS
NGS
--
--
MET Amp
P53 (1)
G796, L792
L792(8), L718 (1), G796(1), PIK3CA (4)
EGFR Amp (29), MET Amp (10), BRAF (3), PIK3CA (9)
Tan ASCO Nazartinib Tissue NGS MTOR del
Chabon Rociletinib Plasma CAPP-Seq
Song Olmutinib Tissue NGS
C797G Menon Osimertinib Tissue NGS EGFR and MYC Amp
L792 Ou ASCO
Chen
Ig Ou
Osimertinib Plasma/Tissue
Plasma
Plasma
NGS
NGS
NGS
C797S (8), PIK3CA (2)
C797S (3)
C797S, G796
L718 Ou ASCO
Bersanelli
Osimertinib Plasma/Tissue
Tissue
NGS
NGS
C797S (1), L792(2), G796(1), KRAS(1)
--
G796 Ig Ou
Ou ASCO
Osimertinib Plasma
Plasma/Tissue
NGS
NGS
L792, C797S
L792, C797S (1), L718(1)
L798 Chabon Rociletinib Plasma CAPP-Seq EGFR Amp
E709K Chabon Rociletinib Plasma CAPP-Seq
L692 V Chabon Rociletinib Plasma CAPP-Seq
EGFR-independent mechanisms of resistance to third generation TKIs
Her 2 Amp Planchard
Oxnard
Ramalingam
Osimertinib Tissue
Plasma/Tissue
Plasma
CGH/FISH
NGS/CGH
NGS
--
--
P53, IDH2
Ortiz-Cuaran Rociletinib/
Osimertinib
Tissue FISH MET Amp(1)
Chabon Rociletinib Plasma CAPP-Seq MET Amp(1), CDKN2A(1), EGFR Amp and PIK3CA(1)
MET Amp Planchard
Ou
Chia
Ramalingam
Ortiz-Cuaran
Piotrowska ASCO
Osimertinib Tissue
Tissue
Tissue
Plasma
Tissue
Plasma/Tissue
NGS/CGH/IHC
ddPCR
NGS
FISH
FISH
--
--
--
RB1 mut, P53
Her2 Amp (1)
--
Tan ASCO Nazartinib Tissue NGS BRAF fusions
Chabon Rociletinib Plasma CAPP-Seq CDKN2A(1), PIK3CA(1), PIK3CA, KRAS and MET Amp(1),Her2 Amp(1)
KRAS mut Ramalingam
Ortiz-Cuaran
Osimertinib Plasma
Tissue
NGS
NGS
CTNNB1
C797S plasma
Chabon Rociletinib Plasma CAPP-Seq MET mut, MET amp, PIK3CA(1), KIT mut(1)
NRAS mut Eberlein Osimertinib Cell lines NGS
BRAF mut Oxnard
Ho et al.
Osimertinib Tissue
Cell lines
NGS
MALDI
--
--
PIK3CA mut Oxnard
Ramalingam
Osimertinib Tissue
Plasma
NGS
NGS
--
P53, PTEN mut, NOTCH
Chabon Rociletinib Plasma CAPP-Seq MET Amp (1), MET Amp, MET mut, KRAS(1), EGFR and Her 2 Amp(1)
PTEN loss Kim Osimertinib Tissue NGS
FGF2-FGFR1
Autocrine loop
Kim
Piotrowska ASCO
Osimertinib Tissue
Plasma/Tissue
NGS
NGS
--
--
SCLC Kim
Ham
Li
Osimertinib Tissue
Tissue
Tissue/Plasma
NGS
NGS
NGS
RB1 loss
EGFR Amp(1)
P53, PTEN, PIK3CA
Piotrowska Rociletinib Tissue/Plasma NGS RB1 loss(1), RB1 mut(1)
  1. Amp amplification, BRAF B-Raf proto-oncogene, CAPP-Seq cancer personal profiling by deep sequencing, CDKN2A cyclin dependent kinase inhibitor 2A, CGH comparative genomic hybridization, CTNNB1 catenin beta 1 gene, ddPCR droplet digital polymerase chain reaction, EGFR Epidermal growth factor receptor, FGF2-FGFR1 FGF2-fibroblast growth factor receptor 1 (FGFR1), FISH fluorescent in situ hybridization, Her2 erb-b2 receptor tyrosine kinase 2, IDH2 isocitrate dehydrogenase 2, IHC immunohistochemistry, KIT KIT proto-oncogene receptor tyrosine kinase, KRAS KRAS proto-oncogene, MALDI matrix assisted laser desorption ionization–time of flight mass, MET MET proto-oncogene, MTOR mechanistic target of rapamysin kinase, mut mutation, MYC MYC proto-oncogene, NGS next generation sequencing, NOTCH NOTCH gene, NRAS NRAS proto-oncogene, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, PTEN Phosphatase and tensin homolog, P53 tumour protein P53, RB1 RB transcriptional corepressor 1, SCLC small cell lung cancer, 3rd gen TKI third-generation tyrosine kinase inhibitor