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Emerging Therapies in Renal Cell Cancer: An Expert Interview With Dr. David I. Quinn

Editor's Note:

Approximately 40,000 new cases of kidney cancer will be diagnosed and about 13,000 people, including adults and children, will die from this disease in 2006 in the United States.[1] Renal cell carcinoma (RCC), the most common type of kidney cancer, accounts for more than 90% of malignant kidney tumors. Metastatic RCC (mRCC) has historically been refractory to conventional chemotherapy. A minority of patients has shown some response to cytokine therapy with interleukin-2 (IL2) or interferon (IFN)-alpha, but associated toxicities can be severe.[2] A better understanding of the molecular basis of clear-cell RCC first led to the clinical development of new agents that inhibit vascular endothelial growth factor (VEGF), including the low molecular weight multitargeted kinase inhibitors, an anti-VEGF antibody, and a mammalian target of rapamycin (mTOR) inhibitor* as second-line agents. New evidence for use of these agents as first-line therapy was presented at the 2006 annual meeting of the American Society of Clinical Oncology. Sally Church, PhD, interviewed David I. Quinn, MBBS, PhD, FRACP, Assistant Professor of Medicine, University of Southern California, Los Angeles, to discuss the emerging body of evidence for use of these agents as first-line therapy, alone or in combination.

Medscape: RCC has historically been resistant to chemotherapy. How is that changing?

Dr. Quinn: You are correct. Although IFN-alpha has been the most commonly used drug for RCC throughout the world, its continued use as a single agent in its current form is in question. The good news is that tyrosine kinase inhibitors (TKIs), such as sunitinib, that predominantly inhibit VEGF-2, are far superior to the old standard IFN-alpha in the treatment of mRCC. Motzer and colleagues[3] randomized 750 previously untreated patients to either sunitinib or IFN-alpha and compared progression-free survival (PFS). PFS was significantly longer (47.3 weeks) in sunitinib-treated patients than in IFN-alpha-treated patients (24.8 weeks, P <>[4] reported preliminary data from a phase 3 , prospective, 3-arm study comparing overall survival (OS) in high-risk, previously untreated patients treated with the mTOR inhibitor temsirolimus, IFN-alpha, or temsirolimus plus IFN-alpha. Although there was a response to the temsirolimus plus IFN-alpha combination, this did not translate into a survival benefit and, in fact, was associated with excess side effects. However, the OS rate was significantly greater when temsirolimus was given as a single agent by weekly infusion at a dose of 25 mg/m2 compared with single-agent IFN-alpha treatment. These results are encouraging because patients with clear-cell RCC make up about 15% of the average oncologist's kidney cancer patient load and until now we have had no effective treatment. These patients usually die an average of 6 months after they develop metastatic disease, so a reduction by about 50% in the odds of death is significant.

Eisen and colleagues[5] presented an update on the sorafenib Treatment Approaches in Renal cancer Global Evaluation Trial [TARGETs], which compared patients who had failed therapy with either sorafenib or placebo. This phase 3 , randomized, double-bind, placebo-controlled study, which was initially presented at the annual ASCO meeting in 2005,[6] showed a highly significant PFS benefit (doubling from 12 to 24 weeks) in the sorafenib group (24 weeks) compared with placebo (12 weeks, P <>

Medscape: What about use of these agents in patients who have failed prior treatment with other agents?

Dr. Quinn: Rini and colleagues[7] reported preliminary interim results of a phase 2 study that evaluated outcomes of sunitinib in bevacizumab-refractory mRCC. Their findings, namely that response rates in patients given sunitinib after they failed bevacizumab therapy are similar to response rates in patients given first-line sunitinib, are encouraging.

Tamaskar and colleagues[8] investigated the anti-tumor effect of sunitinib and sorafenib in a small number of patients who had failed prior treatment with a range of anti-angiogenesis agents given in sequence. They demonstrated that patients can come off one agent and be put on another (even agents of the same class [eg, sorafenib to sunitinib, sunitinib to sorafenib] and bevacizumab) and still respond with disease stabilization or better. I think this is very encouraging. This is contrary to what I believed until several months ago. Our experience at the University of Southern California with sorafenib and sunitinib given in sequence is that patients can be stable on one drug and then be switched to another (ie, because of side effects) achieve a response, and tolerate the therapy in both directions.

Medscape: What about combination therapy?

The combination of erlotinib with bevacizumab in clear-cell RCC was originally explored by Hainsworth and colleagues,[9] in a phase 2 study that showed a fairly high response rate with this combination. In a follow-up study,[10] patients with metastatic RCC were randomized to bevacizumab alone or bevacizumab plus erlotinib. PFS and OS rates were greater than with previous second-line treatment and similar to those achieved with other first-line treatment at this center (Vanderbilt University), reaffirming that bevacizumab has activity against RCC. In North America, the Cancer and Leukemia Group B (CALGB) study of IFN-alpha plus or minus bevacizumab headed by Rini has completed accrual. Results from this study are anticipated by the 2007 annual ASCO meeting. A similar study comparing IFN-alpha with placebo vs bevacizumab is underway in Europe.[11] In general, industry has been slow to support studies of combination therapy with bevacizumab for RCC, perhaps because they are more interested in other major cancer types with a larger market, such as colon, breast, and lung cancers. I would like to see separate trials of sorafenib and sunitinib plus or minus bevacizumab or temsirolimus, but our investigations need to be driven by biologic evaluation in poor-risk and resistant patients to determine optimal therapies.

We also have new data on TKI-plus-cytokine combination therapy from the sorafenib-IFN study by Ryan and colleagues.[12] An overall response rate of 19% is greater than would be expected for either agent alone, but this is a relatively soft end point. We really need to look at complete response and OS rates. The toxicity profile was no worse than expected. In fact, the incidence of hand-foot syndrome, which is one of the major toxicities of sorafenib, was less than expected. Notably, the side effects of INF were not improved and were perhaps a little worse than expected, presumably because the starting dose (10 MIU 3 times weekly) was higher than what we would use in clinical practice and higher than that used in a previous sorafenib-INF trial (3 MIU 3 times weekly with escalation to 6 MIU and 9 MIU over subsequent weeks, based on tolerability), which is also closer to what occurs in practice.

Medscape: What additional advances in the treatment of RCC do you see on the horizon?

Dr. Quinn: We have made progress in terms of disease stabilization across the entire realm, based on the Motzer classification of disease risk. At the moment, there is a suggestion of modest benefit in terms of prolonging survival. However, these drugs do not cure patients and we need to try to cure more patients. I believe that combination therapy is ultimately the way to go, although while this approach may improve outcomes, it may also increase toxicity. This needs to be tested in a series of well-designed trials. Trials designed to look at sequencing are going to be complex and very, very difficult to conduct, so we need to think long and hard before we embark on those. We need to look at the selective utilization of high-dose IL-2 using some of the new markers that increase response prediction from around 5% to 10% to the 30% range. There is a new immunohistochemical marker for tissue called carbonic anhydrase 9 that should be widely available later this year.

*Since this interview was conducted, a new drug application for temsirolimus was submitted to the U.S. Food and Drug Administration, as well as a marketing authorization application to the European Medicines Agency. The manufacturer is seeking an indication for the treatment of patients with advanced RCC.