Targeted therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st-line treatments for patients with advanced
Lung cancer is the leading cause of cancer-related death throughout the whole world. More than half (57%) of all patients with lung cancer have metastasis at the time of diagnosis, and the 5-year survival rate is only 5% (
The 1st-generation EGFR-TKIs, including gefitinib, erlotinib and icotinib, are reversible inhibitors that can inhibit the EGFR tyrosine kinase domain in an ATP-competitive and -reversible manner (
The 2nd-generation EGFR-TKIs, such as afatinib and dacomitinib, were originally designed to overcome the resistance to the 1st-generation EGFR-TKIs (
The so-called 'gatekeeper' T790M mutation increases the competition between ATP and the reversible EGFR-TKIs by exerting effects on both steric hindrance and increased ATP affinity to mutant EGFR receptor, thereby decreasing the efficacy of 1st- and 2nd-generation EGFR-TKIs (
The present review summarizes the emerging evidence on mechanisms of 3rd-generation EGFR-TKI resistance in advanced NSCLC, and outlines the latest clinical strategies used to overcome this problem.
In addition to osimertinib, several other 3rd-generation EGFR-TKIs targeting the T790M mutation (
In 2015, the FDA approved osimertinib for the treatment of patients with metastatic
Overall, osimertinib is a promising 3rd-generation EGFR-TKI in current lung cancer treatment regimens, and osimertinib-based combination therapy deserves broad investigations to improve outcomes in patients with advanced EGFR-mutated NSCLC.
Rociletinib (CO1686) is a small-molecule, orally administered and irreversibly selective EGFR-TKI that inhibits
Abivertinib (AC0010) is one of the 3rd-generation EGFR-TKIs developed in China; it is a pyrrolopyrimidine compound, which is highly selective, irreversible and potent (
Several other 3rd-generation EGFR-TKIs are also under development. Nazartinib (EGF816) is a covalent and irreversible EGFR-TKI. Preliminary results from an open-label, multicenter, phase I/II study of 180 patients at 9 academic medical centers in Europe, Asia and North America demonstrated that nazartinib had an excellent safety profile, with low dermal toxicity and a primary adverse event of maculopapular rash (40%) (
Similar to chemotherapy-associated resistance, resistance to EGFR-TKIs includes both primary (intrinsic) and acquired (secondary) types. The primary type is generally defined as resistance that is present prior to the EGFR-TKI treatment. There are few studies related to primary resistance, and the mechanisms are unclear. Possible causes include
EGFR e20ins occur in ~3% of lung adenocarcinoma patients and 9% of EGFR-mutated tumors. EGFR e20ins block EGFR-TKI binding to EGFR target sites, leading to primary resistance (
BIM is a member of the BCL-2 family and a pro-apoptotic molecule. The
Acquired resistance refers to the evading effects of EGFR-TKIs in tumor cells via alteration of their metabolic pathways after exposure to the drugs. With the application of NGS-based genomic profiling, the mechanisms of 3rd-generation EGFR-TKI resistance have been extensively studied. The acquired resistance of osimertinib as the 2nd- and 1st-line therapy (
Other rare
Patients enrolled in the AURA3 study all developed the T790M mutation after the 1st-line treatment with 1st- or 2nd-generation EGFR-TKIs, and 49% (36/73) of them had loss of T790M after osimertinib resistance (
Le
Amplification of c-Met plays an important role in 1st- and 3rd-generation EGFR-TKI resistance; it functions as a transmembrane receptor tyrosine kinase. When hepatocyte growth factor ligands bind to c-Met, c-Met is activated, inducing homodimerization and phosphorylation of intracellular tyrosine residues, which activates the downstream RAS/ERK/MAPK and PI3K-AKT signaling pathways (
HER2 belongs to the EGFR family.
FGFR signaling pathways regulate cell proliferation, migration, cycle progression, metabolism and survival (
IGF1R is present in numerous cell types in various tissues, such as muscle, cartilage, bone and brain; it is a tyrosine kinases receptor that is involved in the pathogenesis and progression of various malignancies, including lung cancer (
AXL is a member of the receptor tyrosine kinases, which are involved in the regulation of cell survival, proliferation, migration and metabolism. A study by Taniguchi
Acquired resistance to the 3rd-generation EGFR-TKIs is associated with the activation of the RAS-MAPK pathway. BRAF is a serine/threonine protein kinase, which regulates cell survival, proliferation, differentiation and apoptosis, and plays a crucial role in RAS/RAF/MEK/ERK pathways. Nakatani
Phosphatidylinositol-3- kinase catalytic α (
Marcoux
The AURA3 and FLAURA studies demonstrated that the frequency of cell cycle gene alterations was 11 and 12%, respectively, in patients with disease progression after osimertinib treatment as the 1st- or 2nd-line therapy (
Scientists are exploring approaches to overcome the different mechanisms of 3rd-generation EGFR-TKI resistance. Combination of targeted therapies is a promising strategy. For the reversion of 3rd-generation EGFR-TKI resistance, possible strategies to overcome different mechanisms are shown in
If the C797S and T790M mutations are cis-structured (located in the same allele; 85%), patients are resistant to 1st-, 2nd- and 3rd-generation EGFR-TKIs (
When
Against drug resistance due to
Currently, the studies on AXL inhibitors are mainly at the preclinical stages, and there are few clinical trials. Okura
For drug resistance caused by RAS/RAF/MEK/ERK signaling pathway activation, 3rd-generation EGFR-TKIs combined with MEK inhibitors are potential therapeutic strategies. Preclinical studies demonstrated that the combination of osimertinib and selumetinib overcame the resistance caused by
In a recent study, the 3rd-generation EGFR inhibitor WZ-4002 and the FGFR inhibitor dovitinib synergistically inhibited EMT-mediated resistant cell survival and prevented the generation of resistant clones. It was shown that FGFR signaling is critical for the emergence of mesenchymal-like drug tolerant clones. Dual EGFR plus FGFR inhibition might be a promising strategy to avoid resistance (
A recent study included 693 patients with
VEGFR inhibitors have synergistic antitumor effects with EGFR inhibitors. Phase I/II clinical trials of osimertinib in combination with ramucirumab (
A retrospective analysis showed that anti-programmed cell death-1 (PD-1) monotherapy was poorly effective in
For patients who developed SCLC transformation, chemotherapy after osimertinib resistance is an option. Marcoux
The resistance mechanism of 3rd-generation EGFR-TKIs for advanced NSCLC is very complex. The mechanism of 3rd-generation EGFR-TKI resistance in
Not applicable.
JH, YG and CX were responsible for the study conception and design. Administrative support was provided by YG and CX. JH and ZH contributed to the provision of study materials or patients. JH, ZH and LH collected and assembled the data, and JH, ZH and LH were responsible for data analysis and interpretation. All authors helped to write the manuscript and have read and approved the final manuscript. Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
The authors acknowledge that the 2D structures of different EGFR-TKIs were sourced from
anexelekto
B-cell lymphoma-2-like 11
central nervous system
circulating tumor DNA
deletion
EGFR exon 20 insertions
epidermal growth factor receptor-tyrosine kinase inhibitor
epithelial-mesenchymal transition
exon 19 deletion
Food and Drug Administration
fibroblast growth factor 2
fibroblast growth factor receptor
human epidermal growth factor receptor 2
insulin-like growth factor 1 receptor
hepatocyte growth factor receptor
next-generation sequencing
non-small cell lung cancer
objective response rate
overall survival
programmed cell death-1
programmed cell death-ligand-1
progression free survival
phosphatidylinositol-3-kinase catalytic α
squamous cell carcinoma
vascular endothelial growth factor receptor
Chemical structures of different generations of EGFR-TKIs. Chemical structures were sourced from
Mechanisms of primary and acquired 3rd-generation EGFR-TKI resistance in advanced
Mechanisms of acquired 3rd-generation EGFR-TKI resistance in advanced
Molecular mechanisms of acquired 3rd-generation EGFR-TKI resistance. act, activation; NTRK1, neurotrophic receptor tyrosine kinase 1; ALK, anaplastic lymphocyte kinase; ROS1, c-ros oncogene 1, receptor tyrosine kinase; STAT3, signal transducer and activator of transcription 3; EMT, epithelial-mesenchymal transition; SCLC, small cell lung cancer; SCC, squamous cell carcinoma;
Possible overcome strategies to the 3rd-generation EGFR-TKI resistance in advanced
Different generations of EGFR-TKIs.
A, 1st-generation EGFR-TKIs
| |||||
---|---|---|---|---|---|
Drug name | Molecular target | Target binding mode | Resistance mechanisms | Status | Adverse events |
Gefitinib (ZD1839) | EGFR Ex19del, L858R | Reversible; competitive | T790M, EGFR amp, HER2 amp, MET amp | Approved by the FDA in 2005 | Skin rash/acne, abnormal LFT, anorexia ( |
Erlotinib (OSI-774) | EGFR Ex19del, L858R | Reversible; competitive | T790M, EGFR amp, HER2 amp, MET amp | Approved by the FDA in 2003 | Skin rash, abnormal LFT, diarrhea ( |
Icotinib (BPI-2009H) | EGFR Ex19del, L858R | Reversible; competitive | T790M, EGFR amp, HER2 amp, MET amp | Approved by the SFDA in 2011 | Skin rash, cough, diarrhea, abnormal LFT ( |
| |||||
B, 2nd-generation EGFR-TKIs
| |||||
Drug name | Molecular target | Target binding mode | Resistance mechanisms | Status | Adverse events |
Afatinib (BIBW 2992) | EGFR Ex19del, L858R, HER2, HER4, uncommon mutations | Irreversible; covalent | T790M, EGFR amp, HER2 amp, MET amp | Approved by the FDA in 2013 | Diarrhea, paronychia, skin rash ( |
Dacomitinib (PF-00299804) | EGFR Ex19del, L858R, HER2, HER4 | Irreversible; covalent | T790M, EGFR amp, HER2 amp, MET amp | Approved by the FDA in 2018 | Diarrhea, skin rash/acne, paronychia ( |
| |||||
C, 3rd-generation EGFR-TKIs
| |||||
Drug name | Molecular target | Target binding mode | Resistance mechanisms | Status | Adverse events |
Osimertinib (AZD9291) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S, MET amp, EGFR amp, HER2 amp/mut, PIK3CA amp/mut, SCLC transformation | Approved by the FDA in 2015 | Diarrhea, skin rash, dry skin, paronychia ( |
Rociletinib (AVL301/CO1686) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S, EGFR amp, MET amp, HER2 amp, KRAS mut | After phase I/II trial, rejected by the FDA | Hyperglycemia, QTc prolong, cataracts ( |
Abivertinib (AC0010) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S, EGFR amp, MET amp, HER2 amp, KRAS mut | Phase II | Diarrhea, skin rash, abnormal LFT ( |
Nazartinib (EGF816) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S, MET amp | Phase III | Rash, diarrhea, pruritus ( |
Olmutinib (HM61713) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S | Approved by the FDA in 2015 | Diarrhea, skin exfoliation, nausea ( |
Alflutinib (AST2818) | EGFR G719X, Ex19del, L858R, L861Q, T790M | Irreversible; covalent | N/A | Approved in China in 2021 | Diarrhea, skin rash, abnormal LFT ( |
Almonertinib (HS-10296) | EGFR G719X, Ex19del, L858R, L861Q, T790M | Irreversible; covalent | N/A | Approved in China in 2020 | Creatine phosphokinase elevation, skin rash, abnormal LFT, leukopenia ( |
Lazertinib (YH25448/GNS-1480) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | C797S, EGFR amp, PIK3CA, MET amp, HER2 amp | Approved in South Korea in 2021 | Skin rash, pruritus, paresthesia ( |
Naquotinib (ASP8273) | EGFR Ex19del, L858R, T790M | Irreversible; covalent | N/A | Phase III discontinued | Diarrhea, hyponatremia, abnormal LFT, nausea ( |
| |||||
D, 4th-generation EGFR-TKIs
| |||||
Drug name | Molecular target | Target binding mode | Resistance mechanisms | Status | Adverse events |
EAI045 | EGFR L858R, C797S, T790M | Non-ATP- competitive; reversible | N/A | Preclinical ( |
N/A |
BLU-945 | EGFR Ex19del, L858R, C797S, T790M | N/A | N/A | Preclinical ( |
N/A |
TQB3804 | EGFR Ex19del, L858R, C797S, T790M | N/A | N/A | Phase I ( |
N/A |
| |||||
E, Multi-target TKIs
| |||||
Drug name | Molecular target | Target binding mode | Resistance mechanisms | Status | Adverse events |
Brigatinib (AP26113) | EGFR Ex19del, L858R, C797S, T790M | ATP- competitive; reversible | N/A | Approved by the FDA in 2016 | Nausea, diarrhea, headache, creatine phosphokinase elevation ( |
amp, amplification; Ex19del, exon 19 deletion; FDA, Food and Drug Administration; SFDA, Chinese State Food and Drug Administration; LFT, liver function test; mut, mutation; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; QTc, corrected QT interval; SCLC, small cell lung cancer; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2.
Combined therapies to overcome 3rd-generation EGFR-tyrosine kinase inhibitor resistance.
Targeted resistance | Target | Combined strategies | Primary outcomes | Clinical trial identifier | (Refs.) |
---|---|---|---|---|---|
EGFR-dependent resistance | |||||
EGFR C797S, in cis | C797S | Brigatinib + cetuximab | mPFS time of 14 months and an ORR of 60% | None | ( |
Osimertinib + bevacizumab + brigatinib | PR after 1 month of treatment and had fewer |
None | ( | ||
EGFR C797S, in trans | C797S | Osimertinib + erlotinib | PR after 1 month of treatment, PD after 3 months | None | ( |
Osimertinib + geftinib | Clinical improvement within 3 days, PD after 1 month | None | Recruiting | ||
EGFR-independent resistance | |||||
|
c-Met | Osimertinib + crizotinib | PR after 1 month of treatment | None | ( |
Osimertinib + savolitinib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02143466 | ( | ||
Nazartinib + INC280 | Safety (DLTs and MTD) and efficacy (ORR and PFS) | NCT02335944 | None | ||
|
HER2 | Osimertinib + trastuzumab | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT03784599 | None |
Osimertinib + necitumumab + trastuzumab | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT04285671 | None | ||
|
AXL | Osimertinib + DS-1205c | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT03255083 | None |
MEK | Osimertinib + selumetinib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02143466 | None | |
RAS/RAF/MEK/ERK pathway aberrant activation | |||||
|
BRAF | Dabrafenib + trametinib | ORR of 63% and a DCR of 79% | None | ( |
BRAF | Dabrafenib + trametinib | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT04452877/N CT04507919 | None | |
mTOR | Osimertinib + sapanisertib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02503722 | None | |
JAK/STAT3 | JAK | Osimertinib + itacitinib | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT02917993 | None |
Osimertinib + AZD4205 | Safety (incidence of AEs) and efficacy (ORR) | NCT03450330 | None | ||
Histological transformation | |||||
SCLC transformation | None | Etoposide + cisplatin | Responded well to chemotherapy | None | ( |
Etoposide + cisplatin | Clinical response rate of 54% and an estimated mPFS time of 3.4 months | None | ( | ||
Others | |||||
|
RET | Osimertinib + BLU-667 | PR after 2 months of treatment with grade 1 toxicities | None | ( |
|
ALK | Osimertinib + alectinib | PR and a duration of response of 6 months | None | ( |
|
CDK4/6 | Osimertinib + G1T38 | Safety (DLTs and incidence of AEs) and efficacy (PFS and OS) | NCT03455829 | None |
Unknown | VEGFR | Osimertinib + apatinib | Optimal dosage, safety (intensity and incidence of AEs) and efficacy (PFS and OS) | NCT03050411 | None |
Osimertinib+ ramucirumab | Safety (intensity and incidence of AEs) and efficacy (CR, PR, SD, PFS and OS) | NCT02411448 | None | ||
VEGF | Osimertinib + bevacizumab | Safety (MTD and intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT02803203/N CT02971501 | None | |
BCL-2 | Osimertinib + navitoclax | Safety (intensity and incidence of AEs) and efficacy (ORR) | NCT02520778 | None | |
BIM | Osimertinib + aspirin | The mPFS time was 15.3 and 9.3 months for the combination therapy and osimertinib groups, respectively. | None | ( |
mPFS, median progression free survival; ORR, objective response rate; PR, partial response; PD, progressive disease; DLTs, dose limiting toxicities; AEs, adverse events; DCR, disease control rate; OS, overall survival; VEGFR, vascular endothelial growth factor receptor; CR, complete response; SD, stable disease; MTD, maximum tolerated dose; BIM, B-cell lymphoma-2 (BCL-2)-like 11; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; AXL, anexelekto; EGFR, epidermal growth factor receptor.