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Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer

John V. Heymach, Bruce E. Johnson, Diane Prager, Edit Csada, Jaromír Roubec, Milo Peek, Irena pásová, Chandra P. Belani, István Bodrogi, Shirish Gadgeel, Sarah J. Kennedy, Jeannie Hou, Roy S. Herbst

From the Dana-Farber Cancer Institute, Boston, MA; UCLA Medical Center, Los Angeles, CA; University of Szeged, Szeged; National Institute of Oncology, Budapest, Hungary; University Hospital Ostrava-Poruba, Ostrava; University Hospital, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Wayne State University/Karmanos Cancer Institute, Detroit, MI; AstraZeneca, Alderley Park, Macclesfield, United Kingdom; AstraZeneca, Wilmington, DE; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Roy S. Herbst, MD, PhD, Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030-4009; e-mail: rherbst{at}mdanderson.org

Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non–small-cell lung cancer (NSCLC).

Patients and Methods This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m² intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability.

Results In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QT_C) interval.

Conclusion The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

Supported by AstraZeneca. J.V.H. is a Damon Runyon-Lilly Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI 24-04) and the American Society for Clinical Oncology Career Development Award.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain; and the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

ZACTIMA is a trademark of the AstraZeneca group of companies.

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

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