Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer
Open accessAbstract
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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Retrospective analyses of large phase III trials reported inferior ORR than commonly observed in the front-line setting in EGFR-mutated patients treated with EGFR TKIs after chemotherapy.
“However, retrospective analyses of large phase III trials reported inferior ORR than commonly observed in the front-line setting in EGFR-mutated patients treated with EGFR TKIs after chemotherapy [41–44].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [43]
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- Authors
- Hirsch, F. R., Varella-Garcia, M., Bunn, P. A., Franklin, W. A., Dziadziuszko, R., Thatcher, N., Chang, A., Parikh, P., Pereira, J. R., Ciuleanu, T., von Pawel, J., Watkins, C., Flannery, A., Ellison, G., Donald, E., Knight, L., Parums, D., Botwood, N., & Holloway, B.
- Affiliations
- Tata Memorial Hospital (IN)
- From the University of Colorado Cancer Center, Aurora, CO; Medical University of Gdansk, Gdansk, Poland; Christie Hospital, Manchester; AstraZeneca, Macclesfield, United Kingdom; Johns Hopkins Singapore International Medical Center, Singapore; Tata Memorial Hospital, Mumbai, India; Arnaldo Vieira de Carvalho Cancer Institute, São Paulo, Brazil; Oncology Institute Ion Chiricuta, Cluj-Napoca, Romania; and Asklepios Fachkliniken, Gauting, Germany
- Venue
- Journal of Clinical Oncology
- Published
- 2006-11-01
- Volume
- 24
- Issue
- 31
- Pages
- 5034-5042
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2107304950
- Cited by
- 703
- References
- 33
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 12 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 11 · 2017: 16 · 2016: 24 · 2015: 39 · 2014: 43 · 2013: 59 · 2012: 51
- FWCI
- 79.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Association for Cancer Research
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- European Organisation for Research and Treatment of Cancer
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- gefitinib, non-small cell lung cancer, EGFR gene copy number, EGFR expression, EGFR mutation, KRAS mutation, BRAF mutation, Akt phosphorylation, predictive biomarkers, survival outcomes, targeted therapy
- MeSH terms
- Gefitinib, Adult, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Immunohistochemistry, Lung Neoplasms, Male, Middle Aged, Mutation, Phosphorylation, Predictive Value of Tests, Proto-Oncogene Proteins, Quinazolines, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Survival Analysis, Proto-Oncogene Proteins p21(ras), Treatment Outcome, In Situ Hybridization, Fluorescence, ras Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, ErbB Receptors
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