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Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt–Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial

Federico Cappuzzo, Claudia Ligorio, Pasi A. Jänne, Luca Toschi, Elisa Rossi, Rocco Trisolini, Daniela Paioli, Alison J. Holmes, Elisabetta Magrini, Giovanna Finocchiaro, Stefania Bartolini, Alessandra Cancellieri, Fortunato Ciardiello, Marco Patelli, Lucio Crino, Marileila Varella-Garcia

From the Department of Hematology-Oncology, Istituto Clinico Humanitas IRCCS, Rozzano; Department of Medical Oncology, Bellaria-Maggiore Hospital; CINECA-Interuniversity Consortium, Bologna; Department of Medical Oncology, Seconda Universita' di Napoli, Napoli; Department of Medical Oncology, Policlinico Monteluce, Perugia, Italy; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Department of Medicine/Medical Oncology, University of Colorado Cancer Center, Aurora, CO

Address reprint requests to Federico Cappuzzo, MD, Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20089-Rozzano, Italy; e-mail: federico.cappuzzo{at}humanitas.it

Purpose In non–small-cell lung cancer (NSCLC), clinical and biologic predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies, and there is urgent need to validate these results in prospective trials. The ONCOBELL trial is a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt.

Patients and Methods EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and presence of phospho-Akt was evaluated using immunohistochemistry. Additional tests included immunohistochemistry analysis of EGFR, FISH analysis of HER2, and mutation analysis of EGFR, HER2, and K-ras.

Results From November 2004 to February 2006, 183 patients were screened, and 42 patients were enrolled onto the trial. We observed one complete and 19 partial responses, for an overall response rate (RR) of 47.6% (95% CI, 32.5% to 62.7%). Median duration of response was 6.1 months, median time to progression (TTP) was 6.4 months, 1-year survival rate was 64.3%, and median survival time was not reached. EGFR FISH–positive patients, compared with negative patients, had higher RR (68.0% v 9.1%, respectively; P < .001), longer TTP (7.6 v 2.7 months, respectively; P = .02), and a trend for longer survival (median survival not reached v 7.4 months, respectively; P = .3). Therapy was well tolerated, and there were no drug-related deaths. Median follow-up time was too short for significance tests of differences in survival outcomes.

Conclusion Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.

Supported by the Italian Association for Cancer Research (F.C. and L.T.) and National Institutes of Health Grants No. 1K12CA87723-01 (P.A.J.) and 1RO1CA114465-01 (P.A.J.).

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

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