Effective therapy for metastatic renal cancer, whither to now.

The article by Motzer et al, in this issue of Journal of Clinical Oncology, reporting final survival results from the definitive trial of sunitinib versus interferonin metastatic clear cell renal cancer confirms the benefit of this agent and confirms that sunitinib is an appropriate clinical standard of care for initial therapy and the appropriate reference standard for future phase III clinical trials. Perhaps most importantly, sunitinib is representative of the vascular endothelial growth factor (VEGF) pathway inhibitor class of agents that, along with the mammalian target of rapamycin (mTOR) inhibitors, have revolutionized the treatment of renal cancer patients. With this mature data, it is perhaps instructive to review what is known, surmised, and simply speculated in this new era of renal cancer therapy. We should perhaps first analyze whether the data in the Motzer et al report truly define a benefit for patients as the authors claim. In this regard, it is notable that the original primary end point for the study was progression-free survival as measured by standard radiologic imaging and Response Evaluation Criteria in Solid Tumors–based measurements. It is further notable that such measurements are completely arbitrary and have never been demonstrated to be a true surrogate end point in this disease. Thus, although there was a very dramatic improvement in progression-free survival, this alone does not prove that there was a true benefit to patients. The observed improvement in survival, which does define a patient benefit, was only borderline significant by the usual statistical criteria. Importantly, the magic P .05 is in itself somewhat arbitrary and the various statistical approaches that lead to P values either above or below this value is a set of mathematic manipulations that does not change the overall conclusion that there is a small but not vanishingly small probability that the observed differences in survival are simply due to random variation. In general, a single study with an improvement in a validated end point that is significant at an approximate P value of .05 would be insufficient for regulatory authorities or clinicians to change practice. So why is this different? The authors argue that the lack of a more dramatic effect on survival is due to cross-over to sunitinib or other VEGF pathway inhibitor therapy in patients originally randomly assigned to interferon. Although this is a reasonable argument, the lack of a formal cross-over process for all patients in the original protocol makes definitive conclusions difficult. Nevertheless, it is quite notable that the median survival of the control group was more than 21 months, a number that far exceeds the median survival of any prior interferon-based trial in clear cell renal cancer, and exceeded only by the 26-month survival in the sunitinib-treated group. This, along with the authors’ analyses, the published data on quality-of-life differences between patients on sunitinib and interferon, and the available data from other sunitinib trials certainly convinces this author that sunitinib provides a true patient benefit. In this case we should then examine the data more carefully to try to determine which patients are most likely to benefit and are best served by this treatment. First, there are a number of patients that are commonly seen in practice that were excluded from this trial. This includes patients who do not have clear-cell histology, have a performance status of two or higher, have a history of brain metastases, or have had a significant cardiovascular event in the 12 months preceding therapy. In addition, the vast majority of patients enrolled in the Motzer et al trial had a prior nephrectomy. Although there is some data from the phase II and expanded access protocols suggesting that some patients not enrolled in the Motzer et al trial also benefit, there is no supporting phase III data and thus the conclusion that such patients benefit equivalently can only be surmised. These considerations are not simply academic in nature because a significant proportion of patients with metastatic renal cancer have either much worse or much better prognostic features than the majority of the patients enrolled in this trial. Patients with worse prognostic features may be particularly problematic because any lack of efficacy would be further complicated by the potential toxicity of sunitinib. This is not inconsequential, especially if one considers that the incidence of fatigue in the sunitinib group was not significantly different than the incidence of fatigue in the interferongroup, which is a drug that has often been considered quite toxic in large degree due to its propensity to induce fatigue. It is furthermore notable that the incidence of cardiovascular morbidity in a less selected group may be significantly higher than reported here. With the caveat that lack of evidence does not constitute evidence for lack of efficacy, the inability of Motzer et al to identify a survival benefit in the small group of poor-risk patients enrolled in their study is important. This is especially important in light of other phase III data demonstrating a modest improvement in survival of this group of patients with the mTOR inhibitor, temsirolimus. Benefit of sunitinib in patients with poor prognostic features must thus be considered speculative. It is also notable that a survival benefit could not be demonstrated in the good prognosis group, which constituted approximately one third of the patients. Some of these patients may very well have prolonged survival even in the absence of any therapy or may be particularly responsive to immune-based therapies. It should be recalled that the original description of renal cancer prognostic factors by Motzer et al demonstrated that 10% to 20% of patients with good prognostic JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 22 AUGUST 1 2009