The availability of molecularly targeted agents has improved outcomes for patients with renal cell carcinoma (RCC), a disease long considered refractory to systemic therapy. The hypervascularity observed in RCC tumors, which is driven by the inactivation of the vonHippel-Lindau gene, provided a rationale for targeting angiogenesis, in particular vascular endothelial growth factor (VEGF). Bevacizumab, a potent and specific anti-VEGF monoclonal antibody, has demonstrated significant clinical benefits when used in combination with interferon-alfa (IFN-alpha) for the treatment of metastatic RCC in two randomized phase III trials. The use of bevacizumab with IFN-alpha received approval in Europe for the first-line treatment of patients with advanced or metastatic RCC, and more recently this combination was approved for use in patients with mRCC in the United States. Bevacizumab with IFN-alpha has also been recommended by the National Comprehensive Cancer Network for first-line therapy of relapsed or metastatic unresectable RCC with predominantly clear cell histology. Two phase II studies suggest that bevacizumab has single-agent activity, which is characterized by encouraging progression-free survival rates and evidence of tumor regressions in patients with advanced or metastatic RCC. Here we review these trials along with recent and ongoing studies that explore the combination of bevacizumab with other targeted agents, its optimal sequencing with tyrosine kinase inhibitors, and its combination with low-dose IFN-alpha. Collectively, these studies allow the role of bevacizumab-based therapy to be defined in the context of a new and evolving algorithm for the treatment of patients with advanced RCC.
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