Originally published as JCO Early Release 10.1200/JCO.2009.24.3030 on December 28 2009

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Molecular Predictors of Outcome With Gefitinib and Docetaxel in Previously Treated Non–Small-Cell Lung Cancer: Data From the Randomized Phase III INTEREST Trial

From the Centre René Gauducheau, Nantes, France; Princess Margaret Hospital, University of Toronto, Toronto, Canada; McGill University Health Centre, Montreal, Canada; State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong; Shanghai Chest Hospital, Shanghai, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC; Centre Regional de Lutte Contre le Cancer Baclesse, Caen, France; Thoraxklinik Heidelberg; Hospital Grosshansdorf, Grosshansdorf, Germany; AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Wilmington, DE; and The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Corresponding author: Edward S. Kim, MD, M. D. Anderson Cancer Center, Thoracic/Head and Neck Medical Oncology, Box 432, 1515 Holcombe Blvd, Houston, TX 77401; e-mail: edkim{at}mdanderson.org.

Purpose In the phase III INTEREST trial, 1,466 pretreated patients with advanced non–small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes.

Methods Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations.

Results For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation–positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel.

Conclusion These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation–positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.

See accompanying editorial on page 713 and article on page 753

Supported by AstraZeneca.

Presented in part at the 12th World Conference on Lung Cancer, Seoul, Korea, September 2-6, 2007, and the 14th European Cancer Conference, Barcelona, September 23-27, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00076388 [ClinicalTrials.gov] .

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