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

Full 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.

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Author information

Author/s: Hirsch, Fred R (FR); Varella-Garcia, Marileila (M); Bunn, Paul A (PA); Franklin, Wilbur A (WA); Dziadziuszko, Rafal (R); Thatcher, Nick (N); Chang, Alex (A); Parikh, Purvish (P); Pereira, José Rodrigues (JR); Ciuleanu, Tudor (T); von Pawel, Joachim (J); Watkins, Claire (C); Flannery, Angela (A); Ellison, Gillian (G); Donald, Emma (E); Knight, Lucy (L); Parums, Dinah (D); Botwood, Nicholas (N); Holloway, Brian (B);

Affiliation: University of Colorado Cancer Center, PO Box 6511, Mail Stop 8111, Aurora, CO 80045, USA. Fred.Hirsch(-atsign-)UCHSC.edu

Journal and publication information

Publication Type: Clinical Trial, Phase III; Controlled Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol), published in United States. (Language: eng)

Reference: 2006-Nov; vol 24 (issue 31) : pp 5034-42

Dates: Created 2006/10/31; Completed 2006/11/14; Revised 2007/11/15;

PMID: 17075123, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: J Clin Oncol. 2007 May 20;25(15):2144; author reply 2144-5. (PMID: 17513827)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult
Aged
Antineoplastic Agents - therapeutic use
Carcinoma, Non-Small-Cell Lung - chemistry; drug therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Lung Neoplasms - chemistry; drug therapy
Male
Middle Aged

Mutation
Phosphorylation
Predictive Value of Tests
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins c-akt - analysis
Quinazolines - therapeutic use
Receptor, Epidermal Growth Factor - analysis; genetics
Survival Analysis
Treatment Outcome
Tumor Markers, Biological - analysis
ras Proteins

Associated Chemicals: Antineoplastic Agents (0) ; KRAS protein, human (0) ; Proto-Oncogene Proteins (0) ; Quinazolines (0) ; Tumor Markers, Biological (0) ; gefitinib (184475-35-2) ; Receptor, Epidermal Growth Factor (EC 2.7.1.112) ; BRAF protein, human (EC 2.7.1.37) ; Proto-Oncogene Proteins B-raf (EC 2.7.1.37) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37) ; ras Proteins (EC 3.6.5.2)

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