Originally published as JCO Early Release 10.1200/JCO.2008.17.3138 on October 20 2008

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Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

John V. Heymach, Luis Paz-Ares, Filippo De Braud, Martin Sebastian, David J. Stewart, Wilfried E.E. Eberhardt, Anantbhushan A. Ranade, Graham Cohen, Jose Manuel Trigo, Alan B. Sandler, Philip D. Bonomi, Roy S. Herbst, Annetta D. Krebs, James Vasselli, Bruce E. Johnson

From the Dana-Farber Cancer Institute, Boston, MA; Doce de Octubre University Hospital, Madrid; Hospital Clínico Virgen de la Victoria, Málaga, Spain; European Institute of Oncology, Milan, Italy; Universität Mainz III Med. Klinik, Mainz, Germany; University of Texas M.D. Anderson Cancer Center, Houston, TX; Universitatsklinikum of the University of Duisburg-Essen, Essen, Germany; Deenanath Mangeshkar Hospital and Research Center, Pune, India; Mary Potter Oncology Centre, Pretoria, South Africa; Vanderbilt University Medical Center, Nashville, TN; Rush University Medical Center, Chicago, IL; and AstraZeneca, Wilmington, DE

Corresponding author: Bruce E. Johnson, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: bruce_johnson{at}dfci.harvard.edu

Purpose Vandetanib is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The antitumor activity of vandetanib monotherapy or vandetanib with paclitaxel and carboplatin (VPC) was compared with paclitaxel and carboplatin (PC) in previously untreated patients with non–small-cell lung cancer (NSCLC).

Patients and Methods All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded, placebo-controlled, randomized phase II study. Patients were randomly assigned 2:1:1 to receive vandetanib, VPC, or PC. Progression-free survival (PFS) was the primary end point, and the study was powered to detect a reduced risk of progression with VPC versus PC (hazard ratio = 0.70; one-sided P < .2) and to demonstrate noninferiority for vandetanib versus PC. Overall survival was a secondary assessment.

Results The risk of progression was reduced for patients receiving VPC (n = 56) versus PC (n = 52; hazard ratio = 0.76, one-sided P = .098); median PFS was 24 weeks (VPC) and 23 weeks (PC). The vandetanib monotherapy arm (n = 73) was discontinued after a planned interim PFS analysis met the criterion for discontinuation (hazard ratio > 1.33 v PC). Overall survival was not significantly different between patients receiving VPC or PC. Rash, diarrhea, and hypertension were common adverse events; no pulmonary or CNS hemorrhage events required intervention.

Conclusion VPC could be safely administered to patients with NSCLC, including those with squamous cell histology and treated brain metastases. Compared with the PC control arm, patients receiving VPC had longer PFS, meeting the prespecified study end point, whereas those receiving vandetanib monotherapy had shorter PFS.

published online ahead of print at www.jco.org on October 20, 2008.

Supported by AstraZeneca (including editorial assistance provided by John Matthew of Mudskipper Bioscience). J.V.H. is a Damon Runyan-Lilly Clinical Investigator supported in part by the Damon Runyan Cancer Research Foundation (Grant No. CI 24-04) and the American Society for Clinical Oncology Career Development Award.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL (poster); 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain (poster); 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL (poster); and 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea (oral).

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

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