Abstract | PURPOSE: 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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Authors | Daniel B Costa, Kim-Son H Nguyen, Byoung C Cho, Lecia V Sequist, David M Jackman, Gregory J Riely, Beow Y Yeap, Balázs Halmos, Joo H Kim, Pasi A Jänne, Mark S Huberman, William Pao, Daniel G Tenen, Susumu Kobayashi |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 14
Issue 21
Pg. 7060-7
(Nov 01 2008)
ISSN: 1078-0432 [Print] United States |
PMID | 18981003
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Quinazolines
- Erlotinib Hydrochloride
- ErbB Receptors
- Gefitinib
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Topics |
- Adenocarcinoma
(drug therapy, genetics)
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents
(therapeutic use)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics)
- Drug Resistance, Neoplasm
- ErbB Receptors
(antagonists & inhibitors, genetics)
- Erlotinib Hydrochloride
- Female
- Gefitinib
- Humans
- Lung Neoplasms
(drug therapy, genetics)
- Male
- Middle Aged
- Mutation
- Protein Kinase Inhibitors
- Quinazolines
(therapeutic use)
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