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 2Â 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 2Â 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) | |