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Editor's Note:
The treatment of patients with renal cell carcinoma (RCC) -- long a cancer type with limited treatment prospects -- has advanced significantly with the recent introduction of 2 novel targeted therapies, sunitinib and sorafenib. News of the US Food and Drug Administration's (FDA's) approval of an addition to the roster of agents for RCC, temsirolimus, reached the oncology community as physicians arrived at the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1-5, in Chicago, Illinois.
At the ASCO meeting, Medscape's Jill Chamberlain spoke with Robert Figlin, MD, Associate Director for Clinical Research, Comprehensive Cancer Center; Chair, Division of Medical Oncology & Therapeutics Research; and Arthur and Rosalie Kaplan Professor of Medical Oncology at the City of Hope National Medical Center in Duarte, California. Dr. Figlin discussed how the integration of new data from clinical trials and the application of evidence-based medicine should steer oncologists toward the best treatment option for patients with RCC.
Medscape: Results from multiple investigations of both approved and investigational drugs for the treatment of RCC were presented at the 2007 ASCO Annual Meeting. How can medical oncologists translate the key results of these studies into clinical practice?
Dr. Figlin: Whenever possible, physicians should practice evidence-based medicine. To accomplish that goal, the challenge is to consider current evidence about the currently approved drugs as well as data presented at leading-edge conferences such as the ASCO annual meeting, and to integrate that information into their treatment approach.
At this year's ASCO meeting, investigators presented updated results of a trial comparing the kinase inhibitor sunitinib vs interferon alfa in front-line therapy for RCC.[1] This report was a follow-up to results of an important trial published in January 2007 in The New England Journal of Medicine, which demonstrated that sunitinib provides a clear and unequivocal improvement over interferon alfa in patients with metastatic RCC who have favorable or intermediate prognostic features according to the Memorial Sloan-Kettering Cancer Center (MSKCC) classification.[2] In that trial, of the patients who received sunitinib, approximately 45% had objective remission; median progression-free survival (PFS) was 11 months in the sunitinib group compared with 5 months in the interferon alfa group, with a hazard ratio of 0.42 (95% confidence interval [CI], 0.32 to 0.54; P < .001). Overall survival has not yet been reached. Thus, for favorable-risk and intermediate-risk patients with clear-cell RCC, evidence-based medicine dictates that sunitinib is the drug of choice.
According to another significant presentation at the ASCO meeting, a randomized, phase 2 trial of first-line treatment with sorafenib vs interferon alfa in patients with advanced RCC did not achieve its primary end point of PFS.[3] Thus, sorafenib likely is not indicated for RCC in the front-line setting, except for those patients who cannot clinically tolerate sunitinib.
Medscape: Just prior to the ASCO meeting, temsirolimus was approved by the FDA for the treatment of RCC. Where should this new drug be placed within the current treatment algorithm?
Dr. Figlin: On May 31, another paper in The New England Journal of Medicine highlighted the results of a large trial of temsirolimus (a specific inhibitor of the mammalian target of rapamycin kinase), interferon alfa, or both for advanced RCC.[4] In this multicenter, phase 3 trial, patients who received temsirolimus alone had longer overall survival (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; P = .008) and PFS (P < .001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P = .70). Median overall survival times in the temsirolimus, interferon, and combination-therapy groups were 10.9, 7.3, and 8.4 months, respectively.
Immediately before this important study was released, the FDA approved temsirolimus for use in patients with advanced renal cancer. Evidence-based medicine dictates that in the poor-risk RCC patient -- that is, one who meets 3 of 6 modified MSKCC risk criteria -- temsirolimus is the drug of choice. Unlike sunitinib and sorafenib, which are oral agents, temsirolimus is administered intravenously.
Medscape: Bevacizumab has been under investigation in the setting of RCC and a host of other cancer types. Does it appear that this angiogenesis inhibitor will play a key role in the treatment of patients with RCC?
Dr. Figlin: At the ASCO meeting, Escudier presented the results of a trial comparing bevacizumab plus interferon alfa and interferon alfa alone as front-line treatment of RCC.[5] The investigative team reported an improvement in PFS in a patient group that would be comparable to favorable-risk and intermediate-risk patients with clear-cell RCC who received sunitinib. Although final study data are not yet available, the results presented at ASCO raise some interesting questions. First, what is the effect of interferon alfa added to bevacizumab? The response rate achieved with the combination was 31%, compared with 13% for interferon alfa alone. We do not know what the effect of bevacizumab alone might be in untreated patients because no study is presently addressing that issue. Thus, if an oncologist chooses to use bevacizumab in favorable-risk or intermediate-risk patients with clear-cell RCC, it must be combined with interferon alfa to obtain the reported benefit.
Also of concern is that, in the trial, the PFS was investigator-assessed. It would be reassuring if the PFS data were reviewed and confirmed by an independent panel. In addition, some patients died during treatment due to bleeding. Although the frequency of this adverse event was low, if bleeding is indeed a drug-associated complication of bevacizumab treatment, physicians must weigh the potential benefit of the drug against the possible risk of hemorrhage and bleeding.
Medscape: What are some of the overall toxicity issues related to these treatments for RCC?
Dr. Figlin: The toxicity associated with these targeted agents obviously is different from that of chemotherapeutic agents and historical treatments for RCC. Although each agent is associated with its particular toxicities, in general, all of the drugs used to treat patients with RCC are well tolerated.
Medscape: Have any of the currently available drugs for RCC been studied in combination with agents other than interferon?
Dr. Figlin: Historically, medical oncology has taken the position that if 2 individual drugs are effective, the next step is to combine them and assess their interaction. That approach may not hold true for targeted agents. We know from phase 1 trials that combining targeted agents heightens toxicity. However, we must at least raise the question of whether drug A followed by drug B may be as good as A plus B, and we need to develop strategies to test both of those hypotheses. For the practicing oncologist, however, it is not prudent to combine available agents outside of a clinical trial because of the potential for added toxicity.
Medscape: Have there been any recent advances in the second-line treatment of RCC?
Dr. Figlin: In the second-line setting, the treatment decision is straightforward. Sorafenib is clearly the drug of choice because evidence-based medicine has shown us that sorafenib produces a 2-fold improvement in PFS in patients who have failed cytokine therapy and offers the opportunity for a positive result.[6] Data are evolving on use of the currently available targeted agents when another therapeutic choice has failed. Although oncologists may consider sequential drug approaches because there is little else to offer patients, they should be cognizant of the fact that the evidence-based literature demonstrates a lack of knowledge of how best to sequence these drugs. Anecdotal evidence suggests that there may be some clinical benefit associated with sequential treatment, but the magnitude of the effect is unclear.
Medscape: What's ahead in the treatment of RCC?
Dr. Figlin: Further work is needed to refine the optimal dosing for the currently available RCC therapies. Oral agents for RCC are not uniformly absorbed, distributed, and cleared, and pharmacokinetic and pharmacodynamic analyses suggest that several factors may be important. As evidenced by a meta-analysis reported by Houk and colleagues at ASCO, maintenance of higher levels of sunitinib is associated with a superior objective response rate, PFS, and overall survival.[7] Amato reported that dose-escalation strategies for sorafenib might offer benefits over FDA-approved dosages.[8]
The single largest trial in second-line patients with RCC who have failed vascular endothelial growth receptor (VEGFR) therapies is investigating RAD001, another inhibitor of the mammalian target of rapamycin kinase. The study is progressing very rapidly, and accrual may be completed late in 2007. Next year, we may anticipate an ASCO presentation on the efficacy and safety of this agent in VEGFR-resistant patients.
Renal cancer has turned out to be an incredible testing ground for novel therapeutics. We have progressed from no treatment options to a wealth of therapies. Many of us in the field want to ensure that a decade from now, we have not just wasted time determining which of the currently available drugs is best but have found a way to continue the search for a cure. The challenge is to find ways to continue to extend our observations so that in 10 years we are still reporting exciting findings at the Plenary Session at ASCO.
Credit for our past and future research in RCC must go to 3 important groups: patients and families, for participating in clinical trials; renal cell cancer investigators around the world, who are highly collaborative and have worked to advance the treatment for this disease over the past 25 years; and the pharmaceutical industry, which has heard our voice and helped us test these novel drugs.
Supported by an independent educational grant from Pfizer
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