Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer

Fred R. Hirsch, Marileila Varella-Garcia, Paul A. Bunn, Wilbur A. Franklin, Rafal Dziadziuszko, Nick Thatcher, Alex Y Chang, Purvish Parikh, José Rodrigues Pereira, Tudor Ciuleanu, Joachim Von Pawel, Claire Watkins, Angela Flannery, Gillian Ellison, Emma Donald, Lucy Knight, Dinah Parums, Nicholas Botwood, Brian Holloway

Research output: Contribution to journalArticle

Abstract

Purpose: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. Methods: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). Results: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. Conclusion: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Original languageEnglish (US)
Pages (from-to)5034-5042
Number of pages9
JournalJournal of Clinical Oncology
Volume24
Issue number31
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Placebos
Epidermal Growth Factor Receptor
erbB-1 Genes
Gene Dosage
Mutation
Survival
Lung Neoplasms
Biomarkers
Proteins
gefitinib
Survival Analysis
Fluorescence In Situ Hybridization
Immunohistochemistry
Biopsy
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hirsch, F. R., Varella-Garcia, M., Bunn, P. A., Franklin, W. A., Dziadziuszko, R., Thatcher, N., ... Holloway, B. (2006). Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. Journal of Clinical Oncology, 24(31), 5034-5042. https://doi.org/10.1200/JCO.2006.06.3958

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. / Hirsch, Fred R.; Varella-Garcia, Marileila; Bunn, Paul A.; Franklin, Wilbur A.; Dziadziuszko, Rafal; Thatcher, Nick; Chang, Alex Y; Parikh, Purvish; Pereira, José Rodrigues; Ciuleanu, Tudor; Von Pawel, Joachim; Watkins, Claire; Flannery, Angela; Ellison, Gillian; Donald, Emma; Knight, Lucy; Parums, Dinah; Botwood, Nicholas; Holloway, Brian.

In: Journal of Clinical Oncology, Vol. 24, No. 31, 01.11.2006, p. 5034-5042.

Research output: Contribution to journalArticle

Hirsch, FR, Varella-Garcia, M, Bunn, PA, Franklin, WA, Dziadziuszko, R, Thatcher, N, Chang, AY, Parikh, P, Pereira, JR, Ciuleanu, T, Von Pawel, J, Watkins, C, Flannery, A, Ellison, G, Donald, E, Knight, L, Parums, D, Botwood, N & Holloway, B 2006, 'Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer', Journal of Clinical Oncology, vol. 24, no. 31, pp. 5034-5042. https://doi.org/10.1200/JCO.2006.06.3958
Hirsch, Fred R. ; Varella-Garcia, Marileila ; Bunn, Paul A. ; Franklin, Wilbur A. ; Dziadziuszko, Rafal ; Thatcher, Nick ; Chang, Alex Y ; Parikh, Purvish ; Pereira, José Rodrigues ; Ciuleanu, Tudor ; Von Pawel, Joachim ; Watkins, Claire ; Flannery, Angela ; Ellison, Gillian ; Donald, Emma ; Knight, Lucy ; Parums, Dinah ; Botwood, Nicholas ; Holloway, Brian. / Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 31. pp. 5034-5042.
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AU - Franklin, Wilbur A.

AU - Dziadziuszko, Rafal

AU - Thatcher, Nick

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AU - Parikh, Purvish

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AU - Watkins, Claire

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AU - Holloway, Brian

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N2 - Purpose: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. Methods: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). Results: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. Conclusion: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

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