Drug Insight: advances in renal cell carcinoma and the role of targeted therapies

There have been considerable advances in our understanding of renal cell carcinoma, which have been translated into the development of several drugs with proven efficacy, with kinase inhibitors demonstrating significant activity. The authors of this review discuss the targeted agents that have proved efficacious in the difficult-to-treat metastatic setting, and highlight the issues of patient selection, scheduling, dose, duration of treatment, potential combinations and toxicity. In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit. Key Points Immunotherapy can be effective in patients with metastatic RCC Interferon alfa confers a small but significant overall survival advantage in metastatic RCC, but only in a group of patients with good prognostic features A small subset of patients (5%) obtained durable complete remission from treatment with intravenous high-dose bolus interleukin 2 Recent developments in the molecular biology of RCC have led to identification of multiple pathways associated with the development of this cancer Sunitinib, sorafenib, axitinib, temsirolimus and bevacizumab have all shown significant activity with