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Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity

Nilofer S. Azad, Edwin M. Posadas, Virginia E. Kwitkowski, Seth M. Steinberg, Lokesh Jain, Christina M. Annunziata, Lori Minasian, Gisele Sarosy, Herbert L. Kotz, Ahalya Premkumar, Liang Cao, Deborah McNally, Catherine Chow, Helen X. Chen, John J. Wright, William D. Figg, Elise C. Kohn

From the Medical Oncology Branch, Biostatistics and Data Management Section, and Genetics Branch, Center for Cancer Research; Cancer Therapy Evaluation Program, Clinical Pharmacology Program, National Cancer Institute; and Diagnostic Radiology Department, Magnuson Clinical Center, National Institutes of Health, Bethesda, MD

Corresponding author: Elise C. Kohn, MD, Laboratory of Pathology, National Cancer Institute, 10 Center Dr, MSC1500, Bethesda, MD 20892; e-mail: kohne{at}mail.nih.gov

Purpose Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects.

Patients and Methods Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).

Results Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles).

Conclusion Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Both N.S.A. and E.M.P. contributed equally to this work.

Presented in part at 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA.

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

Clinical Trials repository link available on www.JCO.org.

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