Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib

Daniel B. Costa, Kim Son H Nguyen, Byoung C. Cho, Lecia V. Sequist, David M. Jackman, Gregory J. Riely, Beow Y. Yeap, Balazs Halmos, Joo H. Kim, Pasi A. Jänne, Mark S. Huberman, William Pao, Daniel G. Tenen, Susumu Kobayashi

Research output: Contribution to journalArticle

140 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7060-7067
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number21
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Mutation
Disease-Free Survival
Confidence Intervals
gefitinib
Erlotinib Hydrochloride
Exons
Lung Neoplasms
Neoplasms
Research Design
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Costa, D. B., Nguyen, K. S. H., Cho, B. C., Sequist, L. V., Jackman, D. M., Riely, G. J., ... Kobayashi, S. (2008). Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clinical Cancer Research, 14(21), 7060-7067. https://doi.org/10.1158/1078-0432.CCR-08-1455

Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. / Costa, Daniel B.; Nguyen, Kim Son H; Cho, Byoung C.; Sequist, Lecia V.; Jackman, David M.; Riely, Gregory J.; Yeap, Beow Y.; Halmos, Balazs; Kim, Joo H.; Jänne, Pasi A.; Huberman, Mark S.; Pao, William; Tenen, Daniel G.; Kobayashi, Susumu.

In: Clinical Cancer Research, Vol. 14, No. 21, 01.11.2008, p. 7060-7067.

Research output: Contribution to journalArticle

Costa, DB, Nguyen, KSH, Cho, BC, Sequist, LV, Jackman, DM, Riely, GJ, Yeap, BY, Halmos, B, Kim, JH, Jänne, PA, Huberman, MS, Pao, W, Tenen, DG & Kobayashi, S 2008, 'Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib', Clinical Cancer Research, vol. 14, no. 21, pp. 7060-7067. https://doi.org/10.1158/1078-0432.CCR-08-1455
Costa, Daniel B. ; Nguyen, Kim Son H ; Cho, Byoung C. ; Sequist, Lecia V. ; Jackman, David M. ; Riely, Gregory J. ; Yeap, Beow Y. ; Halmos, Balazs ; Kim, Joo H. ; Jänne, Pasi A. ; Huberman, Mark S. ; Pao, William ; Tenen, Daniel G. ; Kobayashi, Susumu. / Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 21. pp. 7060-7067.
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AU - Costa, Daniel B.

AU - Nguyen, Kim Son H

AU - Cho, Byoung C.

AU - Sequist, Lecia V.

AU - Jackman, David M.

AU - Riely, Gregory J.

AU - Yeap, Beow Y.

AU - Halmos, Balazs

AU - Kim, Joo H.

AU - Jänne, Pasi A.

AU - Huberman, Mark S.

AU - Pao, William

AU - Tenen, Daniel G.

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N2 - 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.

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