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New Drugs Bring New Questions

New Drugs Bring New Questions

This article is a review of Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma.

In this issue of ONCOLOGY, Hutson and Figlin provide a timely, cogent, and comprehensive review of recent major progress in the therapy of renal cell cancer with targeted agents.

Important Advances

In a little over 2 years, we have witnessed no less than four positive phase III randomized clinical trials of agents that impact pathways implicated in angiogenesis.[1-4] Each of these agents offers differing but overlapping mechanisms of action and variable but generally tolerable side effects. Each of the drugs sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), and bevacizumab (Avastin) have demonstrated a doubling of progression-free survival when compared to or added to what was considered standard therapy in variably but carefully selected populations of patients with renal cell carcinoma. In each of these trials, the side-effect profiles have been satisfactory, resulting in a net qualify-of-life stabilization or improvement.[5]

Importantly, two of these drugs (those for which we have mature data)—sorafenib and temsirolimus—demonstrate an overall survival benefit of around 3.5 months over standard care.[1,3,6] While this important principle has been validated in separate trials, we await follow-up in the studies involving sunitinib and bevacizumab to see if this will be further borne out.[2] In these latter trials, conducted after the availability of sorafenib, we may not see an overall survival advantage simply because patients in the control arm gained access to sorafenib, diluting the ability of the trial to determine a difference between the arms even if one really existed.

Evidence to support the potential for this effect comes from the crossover that occurred in the Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) trial, where 215 of 450 patients in the placebo arm switched to sorafenib after investigators demonstrated an impressive gain in progression-free survival.[6] Patients crossing over to sorafenib had similar responses and response duration to patients starting on the drug, with a resultant vectoral improvement in their survival as demonstrated by Kaplan-Meier analysis. This may be a testament to the effect of these agents as being relatively independent of timing in the progression of renal cell cancer—an important concept for those of us who are keen to test newer strategies in these patients, either before or after the use of this most recent wave of novel agents.

 Work Undone

As we enthusiastically use these new entities in an uncommon cancer that has previously proven a therapeutic miasma and see some success in other cancers such as hepatocellular carcinoma and gastrointestinal stromal tumor (GIST),[7,8] it is very important that we not lose sight of the work undone, questions unanswered.

First, while these drugs may produce significant periods of disease stability or nonprogression in up to 80% of patients, they are not—at least in the current monotherapeutic dosage schema—curative. This has implications for fiscal cost of therapy and adverse drug effects. It also means that there is little room for self-congratulatory navel-gazing and reinforces the need to seize the momentum from recent trials to do even better for renal cancer patients, by continuing to offer them clinical trials.

Second, the optimal dose of these agents has not been determined. A "one-dose-fits-all" strategy does not consider a paradigm of different body mass indices, varying metabolism, and differential end-organ responses related to tumor response and side effects.

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