Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving field of therapy for metastatic renal cell carcinoma (RCC). Dr. Bukowski has been a leader in the field for nearly 30 years and thus has a unique perspective on the remarkable progress that has been made between first-generation (hormones, chemotherapy, vaccines, interferon), second-generation (high-dose interleukin-2 [IL-2, Proleukin], allogeneic stem cell transplantation), and third-generation (sorafenib [Nexavar], sunitinib [Sutent], temsirolimus [Torisel]) therapies.
Drs. Rini and Bukowski review the fundamental role of the von Hippel-Lindau (VHL) protein in renal cancer. The VHL protein regulates the hypoxia-inducible factor (HIF) protein, and HIF, in turn, regulates nearly 200 genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and a number of other important genes/proteins controlling the growth of renal cancer and normal endothelial cells. Understanding of the biology of renal cancer and the endothelial cell led to the development of antiangiogenic therapy beginning in the late 1990s. Early trials with the aspergillus endothelial cell toxin fumagillin were negative.
However, a sentinel paper by Dr. James Yang and colleagues at the National Cancer Institute (NCI) reported clear-cut responses and stabilization of disease with bevacizumab(Drug information on bevacizumab) (Avastin) compared to placebo. Within that same time period, two small-molecule inhibitors of the VEGF pathway, sorafenib(Drug information on sorafenib) and sunitinib, completed phase I trials[3,4] and began to demonstrate activity in renal cancer phase II trials.
At the June 2004 meeting of the American Society of Clinical Oncology (ASCO), three important papers were presented: Dr. Ratain demonstrated an objective prolongation of time to disease progression with sorafenib in a randomized discontinuation trial, Dr. Hainsworth showed that the combination of bevacizumab and erlotinib (Tarceva) had strong anti-RCC activity, and Dr. Motzer showed the strikingly positive phase II data for sunitinib in RCC. Thus, by 2004 three antiangiogenic agents—bevacizumab, sorafenib, and sunitinib—were known to be active against RCC. In 2006/2007, Dr. Hudes added a fourth agent, temsirolimus, to the list of active agents.
In the ensuing 4 years, we have seen the full publication of four definitive phase III trials in RCC. Sunitinib vs interferon in first-line metastatic disease showed an improvement in the median progression-free survival (PFS) from 5 to 11 months. Sorafenib vs placebo in second-line metastatic disease showed an improvement in median PFS from 2.8 to 5.5 months and an improvement in overall survival from 14.3 to 17.8 months (with censoring before crossover, which reduced the significance of the overall survival). The mammalian target of rapamycin (mTOR)-inhibiting agent temsirolimus vs interferon in first-line poor-risk disease showed an improvement in PFS from 3.1 to 5.8 and an improvement in overall survival from 7.3 to 10.8 months. Bevacizumab/interferon vs placebo/interferon in first-line metastatic disease showed an improvement in median PFS from 5.4 to 10.2 months with no difference in overall survival yet with the median survival being in excess of 19.8 months.
Two other key papers and abstracts in the past 4 years have included a randomized phase II trial led by Dr. Bukowski, showing that bevacizumab had independent activity in first-line RCC therapy that was not enhanced by adding erlotinib, and a 2008 abstract by Dr. Rini and the Cancer and Leukemia Group B (CALGB), showing that bevacizumab/interferon vs interferon in first-line metastatic disease improved median PFS from 5.2 to 8.5 months. In the three studies using interferon as a control, interferon demonstrated a consistent median PFS of about 5 months. In each study of an antiangiogenic agent alone or in combination, the antiangiogenic arm showed a PFS of 8.5 to 11 months. Overall survivals have not yet been reached in most of these studies but are expected to favor antiangiogenic therapy and to range from 15 to 24 months.
Thus, in the past 3 years we have seen dramatic improvement across the board in the management of patients with metastatic RCC. As Drs. Rini, Bukowski, and others point out,[11-15] despite this good news, the sobering reality is that there are very few complete responses, that IL-2 is apparently the only curative therapy, that the cumulative cost and toxicity of these agents is substantial, and that nearly every patient with metastatic disease will require second, third, fourth, or further lines of therapy.
Drs. Rini and Bukowski summarize ongoing clinical investigations of metastatic RCC and point out some substantial issues. For example, we do not yet know which sequence is most effective. Should sorafenib or sunitinib be used first? Clearly, the weight of clinical evidence favors sunitinib, but is that always the case? In the expanded-access studies of these agents, the objective response rates for both drugs were in the single digits.[16,17] What about rapid sequential treatments with the alternative drug (ie, an AB-AB type regimen)? We also do not know the mechanisms of drug resistance, nor do we know how to predict sensitivity of individual patients to these drugs.
The authors comment that the roles of third-line therapy, new drugs, and combination therapy are still unclear. They only briefly mention the use of continuous sunitinib, which is likely to be less toxic and probably equivalent to intermittent sunitinib. A randomized phase II investigation of intermittent vs continuous sunitinib is due to close at the end of April 2008.
Phase II trials of sunitinib plus bevacizumab have shown substantial activity at both the Cleveland Clinic and Memorial Sloan-Kettering. Unfortunately, the Sloan-Kettering data may be showing delayed vascular toxicity in patients with one kidney. The Cleveland Clinic experience in patients with two kidneys (many of whom have nonrenal carcinomas) is showing less toxicity. Thus, a planned randomized phase II trial of sunitinib vs sunitinib plus bevacizumab has not been activated.
Many other doublet trials are underway, but trials of combinations such as bevacizumab/sorafenib and bevacizumab/sunitinib are showing toxicity. Likewise, the late toxicity of sunitinib/temsirolimus and sorafenib/temsirolimus combinations is unknown. Only a few trials of triplets are underway. A trial of bevacizumab, erlotinib, and imatinib (Gleevec) was completed, but the combination was too toxic. Likewise, the addition of epidermal growth factor receptor (EGFR)-inhibiting agents (erlotinib, lapatinib [Tykerb], or cetuximab [Erbitux]) to the anti-VEGF agents is unlikely to be fruitful. A trial of gemcitabine (Gemzar) and capecitabine(Drug information on capecitabine) (Xeloda) with bevacizumab is underway at M.D. Anderson Cancer Center. Overall, more that 350 kidney cancer trials are registered at clinicaltrials.gov.
Other New Agents
Drs. Rini and Bukowski point out that the exciting new tyrosine kinase receptor inhibitors (TKIs) axitinib and pazopanib produce response rates of approximately 40%. However, it should be noted that both cediranib (AZ2171) and the Aveo compound AV951 have activity of a similar magnitude. Moreover, the Amgen drug motesanib is active in thyroid cancer, and the Novartis compound TKI258, which inhibits both FGF and VEGF, may be able to inhibit an escape mechanism of chronic VEGF inhibition, namely FGF upregulation. Lastly, vandetanib (AZ6474) is another TKI in prostate cancer trials, and may have benefit in renal cell carcinoma.
The authors describe the important role in RCC of downstream inhibitors of the VEGF-signaling pathway. They mention the mTOR inhibitors temsirolimus and everolimus (RAD-001, Certican). A phase III trial, RECORD1, randomized metastatic RCC patients with one prior therapy in a 2:1 fashion to either best supportive care or oral RAD-001 at 10 mg/d. The primary endpoint was progression-free survival. The trial was reviewed by the independent data monitoring safety committee on February 25, 2008, and based on that review, the committee ruled that the study should be stopped early due to the demonstrated efficacy of RAD-001.
With the positive results seen in RECORD1, Novartis announced that it will seek regulatory clearance for this drug in the second half of 2008. Several other mTOR inhibitors are in the pipeline, including deforolimus from Ariad, which has been purchased and is being developed by Merck.
Although bevacizumab is the most widely used VEGF antibody, a variety of other agents have been developed to inhibit the VEGF molecule, including the VEGF Trap antibody. There is also a PEGylated anti-VEGF fragment being developed by Celltech and a ribosome active against the VEGF receptor from Sima/Chiron. In addition, several VEGF receptor antibodies are also being developed.
Downstream of the VEGF pathway reside PI3-kinase, AKT, and mTOR, all of which have been targeted in efforts to treat RCC. Particularly notable is the BEZ molecule from Novartis and the enzastaurin molecule from Lilly, both being developed as PI3-kinase inhibitors.
Drs. Rini and Bukowski mention perifosine as an AKT inhibitor. While the response rate to this agent in renal cell carcinoma appears promising (ie, several partial responses among the 13 evaluable patients in a broad phase II trial), the definitive trials have yet to be completed. Protocol 228, which is testing perifosine in patients who have failed sunitinib or sorafenib therapy, has an accrual goal of 48 patients and is rapidly achieving that goal. Protocol 231, in patients who have failed a TKI and/or mTOR inhibitor, is also accruing well. Finally, the perifosine/sorafenib phase I trial mentioned by the authors is now in its fourth dose level and is showing substantial activity in renal cancer.
To summarize, this abundance of newly available agents has made it incumbent upon all physicians who treat renal cancer patients to enter them on clinical trials, if at all possible. It remains unclear what the optimal strategy for clinical investigation in first-, second-, and third-line therapy should be.
The Nevada Cancer Institute has addressed this problem by having a protocol tree in place (Figure 1). This protocol tree allows each patient with kidney cancer who comes to our institute to be entered into a clinical trial whenever possible. Centers with a substantial interest in renal cancer should continue to be focal points for referring these patients. Meanwhile, the survival times and the quality of life of patients with metastatic renal cell carcinoma will continue to improve.
Financial Disclosure: Dr. Vogelzang is on advisory boards for AstraZeneca and Pfizer, has received grants/research support from Bristol-Myers Squibb, Merck, and Sanofi-aventis, and is a member of the speakers bureau for Sanofi-aventis. Dr. Samlowski has been a speaker for Pfizer, Bayer, Novartis, and Wyeth, and has served on advisory boards for Pfizer and Genentech.