Originally published as JCO Early Release 10.1200/JCO.2007.14.5466 on February 2 2009

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Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer: AVAiL

From the Krankenhaus Grosshansdorf, Grosshansdorf; Asklepios Fachkliniken München-Gauting, Muenchen-Gauting; St. Vincentius-Kliniken, Karlsruhe; Heidelberg University Medical Center, Mannheim, Germany; Third Faculty of Medicine, Charles University, Postgraduate Medical School, Prague, Czech Republic; Wielkopolskie Centrum Chorob Pluc i Gruzlicy, Poznan, Poland; Cancer Research Center, Moscow, Russia; McGill University Health Centre–Royal Victoria Hospital, Montreal, Quebec; Princess Margaret Hospital, Toronto, Ontario, Canada; and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Corresponding author: Martin Reck, MD, Department of Thoracic Oncology, Hospital Grosshansdorf, Wohrendamm 80, 22927 Grosshansdorf, Germany; e-mail: dr.martin.reck{at}web.de.

Purpose Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non–small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting.

Patients and Methods Patients were randomly assigned to receive cisplatin 80 mg/m² and gemcitabine 1,250 mg/m² for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351).

Results PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade 3 pulmonary hemorrhage rates were 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation.

Conclusion Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.

Supported by F. Hoffmann-La Roche Ltd.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL, and at the 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea.

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

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