title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.
authors.affiliation: Department of Hematology-Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy. federico.cappuzzo@humanitas.it
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: Claudia
authors.initials: C
authors.lastname: Ligorio
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Luca
authors.initials: L
authors.lastname: Toschi
authors.forename: Elisa
authors.initials: E
authors.lastname: Rossi
authors.forename: Rocco
authors.initials: R
authors.lastname: Trisolini
authors.forename: Daniela
authors.initials: D
authors.lastname: Paioli
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Holmes
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Magrini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: Stefania
authors.initials: S
authors.lastname: Bartolini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cancellieri
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Marco
authors.initials: M
authors.lastname: Patelli
authors.forename: Lucio
authors.initials: L
authors.lastname: Crino
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D012907:Smoking
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib