EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications
Abstract
Lung cancer is the leading cause of cancer-related death. The identification of epidermal growth factor receptor (EGFR) somatic mutations defined a new, molecularly classified subgroup of non-small-cell lung cancer (NSCLC). Classic EGFR activating mutations, such as inframe deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21 are associated with sensitivity to first generation quinazoline reversible EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 insertion mutations, which are typically located after the C-helix of the tyrosine kinase domain of EGFR, may account for up to 4% of all EGFR mutations. Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to clinically achievable doses of reversible (gefitinib, erlotinib) and irreversible (neratinib, afatinib, PF00299804) EGFR TKIs. Growing clinical experience with patients whose tumours harbour EGFR exon 20 insertions corresponds with the preclinical data; very few patients have had responses to EGFR TKIs. Despite the prevalence and biological importance of EEGFR exon 20 insertions, few reports have summarised all preclinical and clinical data on these mutations. Here, we review the literature and provide an update with an emphasis on the structural, molecular, and clinical implications of EGFR exon 20 insertions.
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The frequency and effects of atypical EGFR mutations on drug sensitivity are unknown.
“Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [9]
Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors, including osimertinib.
“Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors1,3,7–10, including osimertinib12.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [9]
Historical data show overall response rates of about 3-8% to first-line erlotinib, gefitinib, or afatinib in patients with EGFR exon 20 insertion mutations.
“Historical data for patients with EGFR exon 20 insertion mutations have shown that overall response rates are approximately 3–8% to first-line therapy with erlotinib, gefitinib, or afatinib16,18.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [18]
Clinical data and prior studies demonstrate limited activity of available EGFR TKIs in NSCLC driven by EGFR exon 20 insertion and validate the need for alternative treatment strategies.
“These clinical data as well as results from prior studies16,18 demonstrate the limited activity of the available EGFR TKIs in NSCLC driven by an EGFR exon 20 insertion and validate the need for alternative treatment strategies for these specific tumors.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [18]
Most exon 20 insertion mutations, except the rare A763_Y764insFQEA, make tumors resistant to the standard first-line EGFR inhibitors erlotinib, gefitinib, and afatinib.
“EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [4]
The two most clinically prevalent Ex20Ins variants, SVD and ASV, are constitutively active in a manner analogous to canonical activating EGFR mutations.
“Our findings provide evidence that the two most clinically prevalent variants of Ex20Ins mutations, SVD (D770_N771InsSVD) and Ex20Ins ASV (V769_D770InsASV) (2,4,18), are constitutively active in an analogous manner to canonical activating-mutations.”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [4]
Ex20Ins mutants are the third most prevalent group of EGFR mutations, accounting for 4-10% of the segment.
“Ex20Ins mutants account for the third most prevalent group of EGFR mutations, representing 4–10% of the segment.”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [4]
The two most prevalent Ex20Ins forms, D770_N771InsSVD and V769_D770InsASV, account for approximately 40% of patients with Ex20Ins mutations.
“the two most prevalent forms of Ex20Ins (D770_N771InsSVD and V769_D770InsASV), which account for approximately 40% of such patients (2,4,18).”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [4]
Most NSCLCs with EGFR exon 20 insertion mutations do not respond radiographically or clinically to gefitinib or erlotinib, with reported response rate below 5%.
“Unlike EGFR exon 19 deletions and L858R–bearing tumors, most NSCLCs with EGFR exon 20 insertion mutations don’t respond radiographically or clinically to gefitinib or erlotinib. The reported response rate (RR) is below 5% and most patients have short intervals of disease control 35.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [35]
The most common exon 20 insertions are post C-helix insertions of 1-4 amino acids, accounting for 80-90% of all exon 20 insertions.
“The most common EGFR exon 20 insertions that have been reported in NSCLC samples are post C-helix insertions of one to four amino-acids, which in aggregate account for 80–90% of all exon 20 insertions 31,32,35.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [35]
EGFR A763_Y764insFQEA accounts for 10-20% of all reported EGFR exon 20 insertions.
“This sequence alteration accounts for 10–20% of all reported EGFR exon 20 insertions 31,32,35.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [35]
Cells bearing Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD, and H773_V774insH are not inhibited by clinically achievable doses of gefitinib, erlotinib, or afatinib.
“We characterized Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD and H773_V774insH using in vitro models and found that cells bearing these mutant EGFR proteins are not inhibited by clinically-achievable doses of gefitinib, erlotinib 12,35,52–54 or the irreversible EGFR inhibitor afatinib 35,55.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [35]
Several studies have shown that 1G EGFR-TKI are less effective in patients with NSCLC harboring uncommon EGFR mutations compared with patients harboring common EGFR mutations.
“Several studies, although very small, have shown that 1G EGFR‐TKI are less effective in patients with NSCLC harboring such uncommon EGFR mutations, compared with patients harboring common EGFR mutations.”
The Ba/F3 cell line has often been used in many studies investigating EGFR mutations.
“the Ba/F3 cell line has often been used in many studies investigating EGFR mutations,24, 27, 36, 41, 42”
Like 1G EGFR-TKIs, afatinib might be less effective for most exon 20 insertions in preclinical and clinical studies.
“In contrast, like 1G EGFR‐TKI, afatinib might be less effective for most exon 20 insertions in preclinical and clinical studies.24, 25, 28, 42, 43”
EGFR mutations shift the equilibrium of protein structures from an inactive state into an active state, resulting in increased and sustained phosphorylation of EGFR and other HER family proteins without ligand stimulation.
“EGFR mutations shift the equilibrium of protein structures from an inactive state into an active state, resulting in the increased and sustained phosphorylation of EGFR and other HER family proteins without ligand stimulation.18”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [18]
Even second-generation TKIs achieve objective response rate of only 10% for Ins20.
“Even 2G‐TKI achieve ORR of only 10%.18, 66”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [18]
Yasuda et al. reported an additional 31 types of Ins20 mutations.
“In addition, Yasuda et al. reported an additional 31 types of mutations.18, 63”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [18]
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- Authors
- Yasuda, H., Kobayashi, S., & Costa, D. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Costa, Daniel B
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 13
- Issue
- 1
- Pages
- e23-e31
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2151016309
- Cited by
- 610
- References
- 16
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 46 · 2023: 37 · 2022: 51 · 2021: 49 · 2020: 47 · 2019: 46 · 2018: 43 · 2017: 42 · 2016: 44 · 2015: 47 · 2014: 45 · 2013: 46 · 2012: 18
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-12-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Conquer Cancer Foundation
- National Institutes of Health
- National Cancer Institute (CA090578, CA126026)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR exon 20 insertion, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, gefitinib, erlotinib, neratinib, afatinib, drug resistance, preclinical models
- MeSH terms
- Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Exons, Humans, Lung Neoplasms, Models, Molecular, Mutation, Phenotype, Protein Conformation, Structure-Activity Relationship, Biomarkers, Tumor, Drug Design, Drug Resistance, Neoplasm, Genetic Predisposition to Disease, Protein Kinase Inhibitors, Precision Medicine, Molecular Targeted Therapy, ErbB Receptors
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