**12. Sequence of targeted therapy**

Currently, we have the fortunate problem of having several agents demonstrating effica‐ cy in the first- and second-line setting, with a number of other small molecule inhibitors that target VEGFR tyrosine kinase being evaluated in mRCC consistently showing activi‐ ty. With similar mechanisms of action, clinical responses have been observed, including in patients that have previously received TKI therapy. Part of the challenge in moving forward is the lack of understanding of the biologic underpinnings of resistance to the currently approved agents and uniform clinical definitions of what truly constitutes treat‐ ment resistance.

Studies combining targeted therapies are being performed with the known caveat that combinations are associated with high financial cost and risk of increased toxicity due to additive and overlapping side effect profiles. Rational combinations of active agents continue to be evaluated. Currently, combinations of targeted therapy remain experimental and they should only be employed in the context of a clinical trial.

Targeted agents are also being studied in the adjuvant setting for patients with resected highrisk RCC. The Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma (ASSURE) intergroup trial randomizes high-risk nephrectomized patients to 1 year of sor‐ afenib, sunitinib or placebo (estimated enrolment: 1332, primary endpoint: disease-free survival (DFS)) (NCT00326898). Other trials such as the phase III sunitinib versus placebo study for the treatment of patients at high risk of recurrent RCC (S-TRAC: estimated en‐ rolment 236, primary endpoint: DFS) (NCT00375674) and the sorafenib versus placebo tri‐ al in patients with resected intermediate or high-risk RCC (SORCE: estimated enrolment 1656, primary endpoint: DFS) (NCT00492258) will further help elucidate the effect of these agents in the adjuvant setting.
