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Originally published as JCO Early Release 10.1200/JCO.2009.22.5250 on June 1 2009 © 2009 American Society of Clinical Oncology.
Effective Therapy for Metastatic Renal Cancer, Whither to NowUniversity of Chicago, Department of Medicine, Chicago, IL
The article by Motzer et al,1 in this issue of Journal of Clinical Oncology, reporting final survival results from the definitive trial of sunitinib versus interferon- We should perhaps first analyze whether the data in the Motzer et al1 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- 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.1 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.3,5,6
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 interferon- 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 features are 10-year survivors, and this is before the availability of the VEGF and mTOR inhibitor pathway inhibitors.9 Given the above noted toxicities, this is a group of patients who should perhaps be considered for observation, surgical resection of oligometastatic disease, or high-dose interleukin-2 therapy. Thus, the benefit of sunitinib therapy for patients with good prognostic features can be surmised, but whether this is the most appropriate initial therapy for any individual patient is speculative. Finally, even in the largest group of intermediate prognosis clear-cell renal cancer patients for whom this article is most applicable, it is important to question whether all patients benefit equivalently or whether any biomarkers can identify a particularly sensitive subgroup. The data to date suggest that simple markers, such as serum or plasma VEGF levels or specific von Hippel-Lindau mutations, are not particularly predictive. However, newer molecular data suggest that additional subtypes exist even within the clear-cell histologic variant and these should certainly be explored for differential benefit from sunitinib and similar agents.10 There is also suggestive data from analysis of various quantitative dynamic contrast enhanced imaging approaches that these modern tools may also provide predictive markers for VEGF-pathway directed agents.11,12 Thus, the benefit of sunitinib as initial therapy in patients with intermediate prognostic disease has been demonstrated, but there is still significant work to be done in regard to identifying patients most likely to enjoy such benefits. In addition to the questions raised here, the development of effective therapy for renal cancer raises a whole host of additional questions which cannot be explored fully within the space here. These include questions of relative efficacy of the various VEGF pathway inhibitors, the role of combination therapy, mechanisms of clinical resistance to VEGF pathway inhibitors, and the role of these agents in the adjuvant setting. Finally, sunitinib and related agents are far from curative. This report does not represent the beginning of the end for new therapies for renal cancers, but the end of the beginning. This author certainly hopes that investigators, clinicians, and patients are as excited as he is about the opportunities for novel translational and clinical research for addressing the host of new questions that have been raised now that effective therapy for this previous recalcitrant disease is available. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Walter M. Stadler, Bayer (C), Onyx (C), Novartis (C), Pfizer (C), Wyeth (C), Genentech (C), Astra-Zeneca (C), Aveo (C) Stock Ownership: Walter M. Stadler, Abbott Honoraria: None Research Funding: Walter M. Stadler, Bayer, Onyx, Novartis, Genentech, Astar-Zeneca, Exilixis, Medarex, Pfizer, Eli-Lilly, ImClone, Amgen Expert Testimony: Walter M. Stadler, Novartis (C) Other Remuneration: None REFERENCES
1. Motzer RJ, Hutson TE, Tomczak P, et al: Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590, 2009. 2. Cella D, Li JZ, Cappelleri JC, et al: Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: Results from a phase III randomized trial. J Clin Oncol 26:3763–3769, 2008. 3. Gore ME, Porta C, Oudard S, et al: Sunitinib in metastatic renal cell carcinoma (mRCC): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis. J Clin Oncol 25:237s; 2007 (suppl) abstr 5010. 4. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124, 2007. 5. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of su11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24, 2006. 6. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516–2524, 2006. 7. Telli ML, Witteles RM, Fisher GA, et al: Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 19:1613–1618, 2008. 8. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281, 2007. 9. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540, 1999. 10. Gordan JD, Lal P, Dondeti VR, et al: HIF-alpha effects on c-myc distinguish two subtypes of sporadic vhl-deficient clear cell renal carcinoma. Cancer Cell 14:435–446, 2008.[CrossRef][Medline] 11. Hahn OM, Yang C, Medved M, et al: Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 26:4572–4578, 2008. 12. Lamuraglia M, Escudier B, Chami L, et al: To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: Pilot study using dynamic contrast-enhanced doppler ultrasound. Eur J Cancer 42:2472–2479, 2006.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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in 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. 
