Combinatorial and Sequential Targeted Therapy in Metastatic Renal Cell Carcinoma

With the approval of several new agents for the treatment of renal cell carcinoma (RCC) since 2005, the outlook for patients with metastatic disease is improving. The three major classes of agents available to clinicians are immunotherapy, antiangiogenic agents, and mammalian target of rapamycin (mTOR) inhibitors. A number of questions arise on how to best use these therapies, including which sequence to use, whether combinations of agents provide superior outcome compared to monotherapy, and whether predictive biomarkers exist to help guide treatment decision making in patients with metastatic RCC. Based on our current knowledge, combination therapy has not yet succeeded in increasing clinical benefit, and is associated with substantial toxicity. Sequencing is generally safe, with the exception of high-dose interleukin-2 following antiangiogenic therapy. As of now, no useful biomarkers exist to guide treatment decisions. With our evolving understanding of RCC tumor biology, we anticipate that new therapeutic targets will be discovered, and predictive biomarkers will be developed that will aid in improving both combination and sequential therapy for this disease.