Sequential therapy with targeted agents in metastatic renal cell carcinoma: beyond second-line and overcoming drug resistance.

Renal cell carcinoma comprises 2-3% of all adult malignancies and its incidence is increasing. Overall survival of patients with advanced disease has increased over the last decade due to the development of many effective targeted agents. Unfortunately, most patients inevitably develop resistance to these agents. While our understanding of the underlying resistance mechanisms has improved, there remain multiple challenges in order to overcome resistance to targeted agents. Sequential and combination therapy with a variety of novel drugs has been evaluated to maintain ongoing clinical benefit and potentially overcome drug resistance. Retrospective data suggest that further anti-angiogenic therapy may be beneficial in advanced renal cell carcinoma after prior progression on two targeted agents with a similar or different mechanism of action. However, further randomised data are needed to better define the role of these agents beyond second-line therapy in the treatment of renal cell carcinoma.