Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer
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Abstract
PURPOSE: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. PATIENTS AND METHODS: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. RESULTS: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). CONCLUSIONS: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed.
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Patients with G719X mutations treated with first-generation EGFR TKIs have lower overall response rates (14-53%).
“lower overall response rate (ORR) (14–53%) in patients harboring G719X mutations, treated with first-generation EGFR TKIs [12,21,35,36]”
The coexistence of multiple EGFR mutations has a reported frequency of 4-14% of all EGFR mutations.
“However, the true incidence of these genetic events is unknown, with a reported frequency of 4–14% of all EGFR mutations [21,36,46,47].”
Several retrospective studies and case reports of first-generation EGFR-TKIs showed inconsistent responses in patients with NSCLC harboring uncommon EGFR mutations.
“Several retrospective studies and case reports of fi rst-generation EGFR-TKIs showed inconsistent responses in patients with NSCLC harboring uncommon EGFR mutations.”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [25]
In preclinical data, osimertinib was found to be active against most uncommon EGFR mutations, apart from exon 20 insertion variants.
“In preclinical data, osimertinib was found to be active against most uncommon EGFR mutations, apart from exon 20 insertion variants”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [25]
Wu et al reported that objective responses to gefitinib or erlotinib were observed in 57.1% of patients with Gly719 or Leu861 mutations, with a PFS of 6.0 months.
“Wu et al 25 reported that objective responses to ge fi tinib or erlotinib were observed in 57.1% of patients with Gly719 or Leu861 mutations, with a PFS of 6.0 months.”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [25]
Wu et al documented an ORR of 53.3% and a PFS of 8.1 months in patients with G719X mutation who were treated with gefitinib or erlotinib.
“Wu et al 25 documented an ORR of 53.3% and a PFS of 8.1 months in patients with G719X mutation who were treated with ge fi tinib or erlotinib.”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [25]
The clinical significance of rare EGFR mutants is not always fully understood, with some variants associated with response to EGFR TKIs (e.g., exon 18 G719X), others with resistance (e.g., exon 20 T790M), and others with uncertain clinical significance.
“The clinical significance of these rare mutants is not always fully understood with some variants associated with response to EGFR TKIs (for instance, exon 18 G719X) other associated with resistance (i.e. exon 20 T790M) and other with uncertain clinical significance [33–35].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [34]
In addition to classic common mutations, ~10% of patients with EGFR mutations may exhibit mutations in codons other than 19 and 21, including exon 18 G719 (~3-4%), exon 20 mutations (~4-5%), uncommon exon 19 insertions, exon 21 L851Q/R, and compound mutations.
“In addition to classic “common mutations” ~10% of patients with EGFR mutations may ehibit mutations in codons other than 19 and 21. Rare mutations could be detected in a small fraction of patients including exon 18 mutations, predominantly at G719 (~3–4%), exon 20 mutations (~4–5%) as well as uncommon mutations in exon 19 (for example, in-frame insertions) and 21 (i.e. L851Q/R), and finally comp”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [34]
Del19 and L858R account for 44.8% (2573/5741) and 39.8% (2283/5741) of EGFR mutations, respectively.
“Del19 and L858R account for 44.8% (2573/5741) and 39.8% (2283/5741) of EGFR mutations, respectively.29, 45, 46, 47, 48”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [45]
There are fewer data on EGFR TKI activity for uncommon EGFR mutations, which occur in about 10% of patients.
“There are fewer data regarding activity of EGFR TKIs for uncommon EGFR mutations, which are found in approximately 10% of patients.[60][61][62]”
Most studies of uncommon EGFR mutations are retrospective case reports and show differential sensitivity by mutation type.
“Most of the studies are retrospective, comprising individual case reports in patients treated with both firstand second-generation TKIs that highlight differential sensitivities based on mutation type.62,63”
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- Authors
- Wu, J.-Y., Yu, C.-J., Chang, Y.-C., Yang, C.-H., Shih, J.-Y., & Yang, P.-C.
- Affiliations
- National Taiwan University Hospital (TW)
- Corresponding author
- Shih, Jin-Yuan
- Venue
- Clinical Cancer Research
- Published
- 2011-06-01
- Volume
- 17
- Issue
- 11
- Pages
- 3812-3821
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2154130790
- Cited by
- 463
- References
- 6
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 18 · 2023: 20 · 2022: 31 · 2021: 36 · 2020: 44 · 2019: 52 · 2018: 28 · 2017: 48 · 2016: 34 · 2015: 35 · 2014: 33 · 2013: 36 · 2012: 13
- FWCI
- 23.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- EGFR mutation, non-small cell lung cancer, tyrosine kinase inhibitors, gefitinib, erlotinib, uncommon EGFR mutations, exon 20 insertion, exon 19 deletion, L858R, T790M, treatment response, progression-free survival
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, Sequence Deletion, Amino Acid Substitution, Protein Kinase Inhibitors, ErbB Receptors
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