Table 2. EGFR-independent mechanisms of resistance to third-generation EGFR-TKIs.
| Mechanism | Author | Sample | N° of patients | T790M | Method | Other mechanisms associated | 3rd TKI |
|---|---|---|---|---|---|---|---|
| HER2 amplification | Planchard et al. [2015] (25) | Tissue | 1 | Absent | CGH/FISH | — | Osimerinib |
| Oxnard et al. [2015] (26) | Plasma/tissue | 2 | Absent | NGS/CGH | — | Osimertinib | |
| Chabon et al. [2016] (11) | Plasma | 4 | Present [3]; absent [1] | CAPP-Seq | MET amp [1], CDKN2A mut [1], EGFR amp and PIK3CA mut [1] |
Rociletinib | |
| Ortiz-Cuaran et al. [2016] (13) | Tissue | 3 | Present | FISH | MET amp [1] | Rociletinib/Osimertinib | |
| MET amplification | Planchard et al. [2015] (25) | Tissue | 1 | Absent | NGS/CGH/IHC | — | Osimertinib |
| Ou et al. [2016] (27) | Tissue | 1 | 3% | NGS | — | Osimertinib | |
| Chia et al. [2016] (17) | Tissue | 1 | Absent† | ddPCR | — | Osimertinib | |
| Ortiz-Cuaran et al. [2016] (13) | Tissue | 3 | Present | FISH | HER2 amp [1] | Osimertinib | |
| Chabon et al. [2016] (11) | Plasma | 11 | Present [7]; absent [4] | CAPP-Seq | CDKN2A mut [1]; PIK3CA mut [1]; PIK3CA, KRAS and MET mut [1]; HER2 amp [1] |
Rociletinib | |
| PIK3CA mutations | Chabon et al. [2016] (11) | Plasma | 5 | Present [4]; absent [1] | CAPP-Seq | MET amp [1]; MET amp, KRAS and MET mut [1]; EGFR and HER2 amp [1] |
Rociletinib |
| Oxnard et al. [2015] (26) | Biopsy | 1 | Absent | NGS | — | Osimertinib | |
| PTEN loss | Kim et al. [2015] (28) | Tissue | 1 | Present | NGS | — | Osimertinib |
| RAS-MAPK pathway activation | |||||||
| KRAS mut | Ortiz-Cuaran et al. [2016] (13) | Tissue | 1 | Absent | NGS | C797S in plasma | Osimertinib |
| Chabon et al. [2016] (11) | Plasma | 3 | Present | CAPP-Seq | MET amp, PIK3CA mut and MET mut [1]; KIT mut [1] |
Rociletinib | |
| BRAF mut | Oxnard et al. [2015] (26) | Tissue | 1 | Absent | NGS | — | Osimertinib |
| MAPK1/AKT3 overexpression | Kim et al. [2015] (28) | Tissue | 1 | Absent | NGS | — | Osimertinib |
| FGF2-FGFR1 autocrine-loop | Kim et al. [2015] (28) | Tissue | 1 | Absent | NGS | — | Osimertinib |
| SCLC transformation | Piotrowska et al. [2015] (16) | Tissue | 2 | Absent | NGS | — | Rociletinib |
| Kim et al. [2015] (28) | Tissue | 1 | Absent | NGS | — | Osimertinib | |
| Ham et al. [2016] (29) | Tissue | 2 | Absent | NGS | EGFR amp [1] | Osimertinib | |
| EMT | Walter et al. [2013] (30) | NCI-H1975 cells | Pre-clinical | Present | RNA-seq | — | Rociletinib |
| NRAS mutation/CNG | Eberlein et al. [2015] (31) | PC9 cell lines | Pre-clinical | — | NGS | — | Osimertinib |
| IGF1R activation | Park et al. [2016] (32) | PC9 cell lines | Pre-clinical | — | Western blot | — | WZ4002 |
The number of patients with each specific associated resistance mechanism is indicated in parenthesis. †, absent also in plasma sample. amp, amplification; CAPP-Seq, cancer personal profiling by deep sequencing; CGH, comparative genomic hybridization; ddPCR, droplet digital polymerase chain reaction; CNG, copy number gain; mut, mutation; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; NGS, next generation sequencing; SCLC, small cell lung cancer; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; IGF1R, insulin-like growth factor-1 receptor; EMT, epithelial-mesenchymal transition; FGFR1, fibroblast growth factor receptor 1; HER2, erb-b2 receptor tyrosine kinase 2.