Molecular biomarkers in non-small-cell lung cancer : a retrospective analysis of data from the phase 3 FLEX study

O'Byrne, Kenneth J., Gatzemeier, Ulrich, Bondarenko, Igor, Barrios, Carlos, Eschbach, Corinna, Martens, Uwe M., Hotko, Yevhen, Kortsik, Cornelius, Paz-Ares, Luis, Pereira, Jose R., von Pawel, Joachim, Ramlau, Rodryg, Roh, Jae-Kyung, Yu, Chih-Teng, Stroh, Christopher, Celik, Ilhan, Schueler, Armin, & Pirker, Robert (2011) Molecular biomarkers in non-small-cell lung cancer : a retrospective analysis of data from the phase 3 FLEX study. The Lancet Oncology, 12(8), pp. 795-805.

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Background: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting.

Methods: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with, number NCT00148798.

Findings: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16).

Interpretation: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Funding: Merck KGaA. © 2011 Elsevier Ltd.

Impact and interest:

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ID Code: 65284
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: cetuximab, cisplatin, navelbine, adult, aged, article, cancer chemotherapy, cancer survival, codon, controlled study, copy number variation, drug efficacy, EGFR gene, female, fluorescence in situ hybridization, gene, gene expression, gene mutation, human, human tissue, immunohistochemistry, KRAS gene, lung non small cell cancer, major clinical study, male, multiple cycle treatment, mutational analysis, overall survival, phase 3 clinical trial (topic), polymerase chain reaction, predictive value, priority journal, prognosis, progression free survival, PTEN gene, retrospective study, treatment outcome, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Clinical Trials, Phase III as Topic, Genetic Predisposition to Disease, Humans, Lung Neoplasms, Neoplasm Staging, Proto-Oncogene Proteins, ras Proteins, Receptor, Epidermal Growth Factor, Retrospective Studies, Tumor Markers, Biological, Vinblastine
DOI: 10.1016/S1470-2045(11)70189-9
ISSN: 1470-2045
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2011 The Lancet Publishing Group
Deposited On: 11 Dec 2013 01:04
Last Modified: 13 Mar 2014 23:26

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