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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