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Gastrointestinal Cancer

The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer

^aDuke University, Durham, North Carolina, USA; ^bGenentech, Inc., South San Francisco, California, USA

Key Words. Bevacizumab • Vascular endothelial growth factor • Colorectal cancer • Survival • Fluorouracil • Angiogenesis inhibitors

Correspondence: Herbert I. Hurwitz, M.D., Duke University Medical Center, Division of Hematology & Oncology, PO Box 3052, Durham, North Carolina 27710-0001, USA. Telephone: 919-681-5257; Fax: 919-684-9712; e-mail: hurwi004{at}mc.duke.edu

Received September 29, 2008; accepted for publication November 25, 2008; first published online in THE ONCOLOGIST Express on January 14, 2009.

Disclosures

Herbert I. Hurwitz: Consultant/advisory role: Genentech, Roche, Amgen; Honoraria: Genentech, Roche; Research funding/contracted research: Genentech, Roche, Amgen, Sanofi, Bristol-Myers Squibb, Imclone, Sunesis, Cephalon; Jing Yi (and spouse); Employment/leadership position: Genentech; William Ince: Ownership interest: Genentech; William F. Novotny: Employment/leadership position: Genentech; Ownership interest: Genentech; Oliver Rosen: Employment/leadership position: Genentech

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers.

Purpose. Mutations of the K-ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K-ras mutations are a negative predictor of clinical benefit from anti–epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K-ras mutation status.

Patients and Methods. Additional statistical analyses were done with data from K-ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K-ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression-free survival (PFS), OS times, and objective response rates were compared.

Results. K-ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab-treated patients with wild-type (wt)- (13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)-K-ras (9.3 versus 5.5 months; hazard ratio 0.41, p = .0008). A significantly higher response rate for IFL plus bevacizumab was observed only in wt-K-ras patients (60.0% versus 37.3%, p = .006) compared with 43.2% versus 41.2% in the m-K-ras group.

Conclusion. Bevacizumab provides significant clinical benefit in patients with mCRC expressing either mutant or wild-type K-ras.

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