**13. Combination therapy**

One of the next directions in the therapy of advanced RCC involves the combination of several targeted agents to better inhibit a single pathway at several different levels or inhibition at the same level of several pathways mediating different effects. As combinations of targeted agents undergo investigation, it will be critical for these combinations to demonstrate clinical benefit above and beyond those of sequential monotherapy with the same agents, in order to justify the added toxicity and risk. Thus, prospective data in this regard are critical, and some data have recently emerged.

Combinations of VEGF-targeting agents have undergone initial testing. Several combina‐ tions of these targeted agents were studied, including temsirolimus with either bevacizu‐ mab or sorafenib. Bevacizumab was also combined with sunitinib, and PTK787/ ZK222584. These combinations have frequently demonstrated enhanced toxicity, prevent‐ ing the use of the maximum single-agent doses. However, temsirolimus and bevacizu‐ mab in combination could be given at full doses of each agent without enhanced toxicity and with encouraging clinical activity.

The combination of sorafenib and bevacizumab showed preliminary evidence of antitumor activity, but the full doses of each agents were not reached due to dose-limiting toxicity related primarily to hand-foot syndrome, functional stomatitis, anorexia, and fatigue.

Additional preclinical data have described potentially favorable immunomodulation with sunitinib therapy. Such data may provide a rationale for combination strategies with immu‐ notherapy to optimize antitumor effect.

At this point, such combinations cannot be recommended for routine use outside of a clinical trial setting.A greater understanding of the pleiotropic effects of targeted agents is needed to rationally build combinations.
