The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.
This article is a review of Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma.
In this issue of ONCOLOGY, Hutson and Figlin have done a fine job of summarizing areas of recent interest in the management of advanced renal carcinoma (RCC). They clearly show that targeted and rational approaches to the therapy of this disease, predicated on an improved understanding of its underlying biology, have led to the current state of increasing treatment success. As they note, a panoply of therapeutic agents are available, mostly focused on the mechanisms that broker the role of the tumor's vascular investment, but also reflecting the promiscuous molecular connections and relationships of genes that interact with VHL, tyrosine kinase inhibitors, mTOR, and so forth.[1-3] We are even beginning to understand some of the genetic aberrations in VHL that are associated with an increased chance of success.
The situation for patients with RCC is the most promising it has been for the past half-century. What a pity that Dr. Pieter DeMulder, an outstanding Dutch contributor to the field, succumbed to this aggressive disease before he was able to see the full gains of the work by the superb clinical research teams in genitourinary oncology.
So how do we now move forward? We are in the curious situation that we have 20 years of published "negative" results from Ron Bukowski, Bob Figlin, and Bob Motzer, who have become legendary for their commitment to stringent, high-quality research to overcome this disease. The fact that they have spent large parts of their careers honestly reporting an absence of progress gives them great credibility today when they document real progress. The promise that they have each seen in the current set of angiogenesis-active and tyrosine-kinase-inhibiting agents is believable. Another unique feature in this field is that we have a functioning, effective, and highly useful "old boy" network, including these fine researchers and their international collaborators, such as Escudier, Eisen, and others. These researchers are well positioned to identify the most exciting agents, and to develop highly effective collaborative relationships that will allow our patients to receive the maximum benefit as quickly as possible.
The way forward will be to execute well-crafted, statistically valid randomized clinical trials that will address some of the following topics:
• What is the "best agent"?
• What is the "best sequence"?
• Is multiagent superior to single-agent therapy?
• Does sequence matter?
• Is there a "best agent" and does it matter in this context?
• What are the mechanisms that underly success?
• What are the mechanisms that underly failure?
Time for a Consensus Conference?
There is a bit of a tendency for some regulatory agencies to address their lack of fiscal resources by seeking quick gains-for example, promoting the underpowered, randomized phase II design, in which insufficient numbers of patients are allocated to multiple combinations of therapy with agents for which we don't understand the relevant interactions, opposing mechanisms of function, and other confounding variables. Quite reasonably, the pharmaceutical industry is committed to reaping the rewards of expensive and successful research programs, and drug manufacturers will try to ace each other in demonstring the purported unique benefits of their own favored preparations.
Perhaps now is the time for a consensus conference, driven by the icons of the research field, with invitations extended to the important research and regulatory agencies and participation by the pharmaceutical companies. The agenda should be set by those who hold the welfare of patients to be of paramount importance, and who are committed to conducting responsible, reproducible research. If the coterie of Bukowski, Figlin, Motzer, and their friends take up this challenge, they might be able to refine the paradigm and bring patient welfare back to center stage. These physicians have made a lifetime commitment and proven their worth in this arena. Hopefully, they will read this editorial and act upon it.
-Derek Raghavan, MD, PhD
1. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006.
2. Motzer RJ, Hutson TE, Tomczak P, et al: Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. N Engl J Med 356:115-124, 2007.
3. Escudier B, Eisen T, Stadler WM, et al: Treatment Approaches in Renal cancer Global Evaulation Trial (TARGETs): A randomized, double-blind, placebo-controlled phase III trial of sorafenib, an oral multi-kinase inhibitor in advanced renal cell carcinoma. N Engl J Med 356:125-134, 2007.
4. Choueiri TK, Vaziri SA, Rini BI, et al: Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (RCC) (abstract 5012). J Clin Oncol 25(18S):238s, 2007.
5. Raghavan D: An essay on rearranging the deck chairs: What's wrong with the cancer trials system? Clin Cancer Res 12:1949-1950, 2006.