Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib Journal Article
| 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. |
| Article Title: | Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib |
| Abstract: | 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/di n 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 andsu bsequently 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 L85 8R-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 mutatedt umors 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 inhibitedby clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated. ©2008 American Association for Cancer Research. |
| Keywords: | adult; cancer survival; treatment response; aged; aged, 80 and over; middle aged; gene mutation; genetics; mutation; disease course; erlotinib; drug withdrawal; antineoplastic agents; antineoplastic agent; adenocarcinoma; gene amplification; protein kinase inhibitor; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; receptor, epidermal growth factor; drug effect; drug resistance; drug resistance, neoplasm; cetuximab; cancer resistance; protein kinase inhibitors; lung tumor; drug antagonism; gefitinib; drug blood level; drug substitution; quinazolines; quinazoline derivative; scatter factor receptor |
| Journal Title: | Clinical Cancer Research |
| Volume: | 14 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-11-01 |
| Start Page: | 7060 |
| End Page: | 7067 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-08-1455 |
| PUBMED: | 18981003 |
| PROVIDER: | scopus |
| PMCID: | PMC2596582 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 32" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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