The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib
Open accessAbstract
Purpose: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Experimental Design: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification. Results: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
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“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 [52]
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Self-citationPaclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer
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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
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Metadata
- Authors
- Costa, D. B., Nguyen, K.-S. H., Cho, B. C., Sequist, L. V., Jackman, D. M., Riely, G. J., Yeap, B. Y., Halmos, B., Kim, J. H., Jänne, P. A., Huberman, M. S., Pao, W., Tenen, D. G., & Kobayashi, S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Yonsei University (KR)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Memorial Sloan Kettering Cancer Center (US)
- 6Case Western Reserve University, Cleveland, Ohio
- 3Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts;
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2008-11-01
- Volume
- 14
- Issue
- 21
- Pages
- 7060-7067
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2596582
- OpenAlex
- W2154226624
- Cited by
- 171
- References
- 67
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 9 · 2018: 4 · 2017: 6 · 2016: 14 · 2015: 10 · 2014: 15 · 2013: 18 · 2012: 24
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pfizer
- AstraZeneca
- National Institutes of Health
- Genentech
- National Cancer Institute (2PA50-CA09057806, R01CA114465, P50CA090578, K99CA126026, P20CA090578)
- 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
- erlotinib, gefitinib, EGFR mutation, non-small cell lung cancer, tyrosine kinase inhibitor resistance, T790M mutation, MET amplification, exon 19 deletion, L858R, progression-free survival, drug dose comparison
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors
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