Compound EGFR Mutations and Response to EGFR Tyrosine Kinase Inhibitors
Open accessAbstract
Background Non-small-cell lung cancers (NSCLCs) containing EGFR mutations are exquisitely sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions), and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations-where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance-and their pattern of response/resistance to EGFR TKIs are less well described.Methods We analyzed the EGFR mutation pattern of 79 cases of NSCLC harboring EGFR mutations and compiled the genotype-response data for patients with NSCLCs with compound EGFR mutations treated with EGFR TKIs.Results Of the 79 EGFR-mutated tumors identified, 11 (14%) had compound mutations. Most involved the EGFR TKI-sensitizing G719X (n = 3, plus S768I or E709A), L858R (n = 4, plus L747V, R776H, T790M, or A871G), L861Q (n = 1, plus E709V), and delL747_T751 (n = 1, plus R776H). Eight patients received an EGFR TKI: three cases with G719X plus another mutation had partial responses (PRs) to erlotinib; of three cases with L858R plus another mutation, two displayed PRs and one (with EGFR-L858R+A871G) progressive disease (PD) to erlotinib; one NSCLC with EGFR-L861Q+E709A and one with delL747_T751+R776S had PRs to EGFR TKIs.Conclusion Compound EGFR mutations comprised 14% of all mutations identified during routine sequencing of exons 18-21 of EGFR in our cohort. Most patients with an EGFR TKI-sensitizing mutation (G719X, exon 19 deletion, L858R, and L861Q) in addition to an atypical mutation responded to EGFR TKIs. Reporting of the genotype-response pattern of NSCLCs with EGFR compound and other rare mutations, and the addition of this information to searchable databases, will be helpful to select the appropriate therapy for EGFR-mutated NSCLC.
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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].”
The G719X + S768I compound mutation (about 1% of all EGFR mutations) is sensitive to first-generation EGFR TKIs but to a lesser extent than classic mutations, with ORR approximately 50% and median PFS of 8-10 months.
“One of the most frequent compound mutations is the G719X + S768I (about 1% of all EGFR mutations) [37,84], which has been shown to be sensitive to the first-generation EGFR TKIs, but to a lesser extent than classic mutations (ORR approximately 50% and median PFS of 8–10 months) [12,33,46].”
Objective response rate to first-generation TKIs in S768I and L861Q tumors were only 42% and 39%, respectively.
“ORR to 1G‐TKI in S768I and L861Q tumors were only 42 and 39%, respectively (Table 3).26, 29, 61, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [26]
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- Authors
- Kobayashi, S., Canepa, H. M., Bailey, A. S., Nakayama, S., Yamaguchi, N., Goldstein, M. A., Huberman, M. S., & Costa, D. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Costa, Daniel B.
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 8
- Issue
- 1
- Pages
- 118-122
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC3531043
- OpenAlex
- W1994499102
- Cited by
- 213
- References
- 17
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 23 · 2023: 24 · 2022: 23 · 2021: 18 · 2020: 17 · 2019: 18 · 2018: 18 · 2017: 15 · 2016: 13 · 2015: 11 · 2014: 11 · 2013: 5
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA090578, R00CA126026, R01CA169259, P50CA090578, K99CA126026, P20CA090578, CA126026)
- 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
- compound EGFR mutations, EGFR tyrosine kinase inhibitors, non-small cell lung cancer, EGFR mutation, L858R, L861Q, G719X, exon 19 deletion, T790M, erlotinib, treatment response, drug resistance, S768I
- MeSH terms
- Erlotinib Hydrochloride, Aged, Aged, 80 and over, Base Sequence, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, Exons, Female, Genotype, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Mutagenesis, Insertional, Sequence Deletion, Protein Kinase Inhibitors, ErbB Receptors
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