Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

Greater insight into the biology of renal cell carcinoma (RCC) has expanded treatment options in metastatic RCC (mRCC). Since 2005, seven targeted agents have been approved by the US Food and Drug Administration (US FDA) for the management of mRCC, but little evidence exists on combining these therapies together or with novel agents, traditional immunotherapies, or chemotherapeutic drugs.

In theory, combining targeted therapies may provide more complete blockade of aberrant signaling ultimately leading to the potential for additive or synergistic effects. Concomitant targeted therapies may also have the potential to combat resistance that inevitably emerge with single-agent targeted therapies over time. Evidence suggests that resistance is mediated by changes which arise within the tumor and in its surrounding microenvironment. Such changes allow for continued proliferation and growth independent of VEGF. It is hypothesized that signaling upstream of receptor blockade could also drive tumor growth independent of usual aberrant proliferative pathways. Hypoxia-inducible factor (HIF), protein kinase B (AKT), and other parallel and upstream pathways likely contribute to resistance [1]. Combination and/or sequential therapy targeting elements independent of classical VEGF pathways may combat resistance, while potentially exhibiting greater efficacy than single-agent therapy. But, despite potential for great disease control in this area, researchers are ultimately challenged by the greater toxicities that have arisen in many trials attempting to combine targeted agents.

Likewise, although sequential therapy with targeted agents following progression on initial treatment is now the standard of care in mRCC, there is only scant evidence on how agents should be used in sequence to optimize treatment following progression on a first-line agent. Here we review the relevant literature and ongoing trials in this area and discuss future opportunities for continued investigation.

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