One drug of interest has been sunitinib, an agent targeting the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR), proteins that promote angiogenesis and cell proliferation. In a phase 2 study of sunitinib in 63 cytokine-refractory patients with metastatic renal cell carcinoma, tumor shrinkage (or partial response) occurred in 40% of patients (Motzer RJ et al. J Clin Oncol. 2006;24:16-24). A larger phase 2 trial with more than 100 patients conducted to confirm the antitumor efficacy of single-agent sunitinib found a 34% partial response rate and a median progression-free survival of 8.3 months for patients taking the drug (Motzer RJ et al. JAMA. 2006;295:2516-2524). The results led to sunitinib's approval by the US Food and Drug Administration in January as a second-line treatment for advanced renal cell carcinoma in patients whose cancer had progressed after treatment with standard immunotherapies, interferon alfa or interleukin-2. These therapies have less than a 15% response rate (Motzer RJ et al. J Clin Oncol. 2002;20:289-296; Fyfe G et al. J Clin Oncol. 1995;13:688-696). However, so far, long-term survival has only been reported with high-dose interleukin-2 treatment (Rosenberg SA et al. JAMA. 1994;271:907-913). Sunitinib is thought to provide its potential beneficial effects because many renal cancer cells produce excess VEGFR and PDGFR.

Investigators are now conducting a randomized phase 3 trial to compare the efficacy and safety of first-line sunitinib with interferon alfa. A total of 750 treatment-naive patients enrolled from August 2004 to October 2005 were randomly assigned to receive sunitinib or interferon alfa. Patients in both groups received repeated 6-week cycles of therapy, and data were collected until November 2005.

At the time of analysis, responses were assessed for 662 patients. Sixty-six percent of patients assigned to the sunitinib group were continuing treatment compared with 34% of patients assigned to interferon alfa; 45% of patients taking interferon alfa discontinued treatment due to progressive disease vs 25% taking sunitinib. Eight percent of participants in the sunitinib group and 13% in the interferon alfa group withdrew from the study due to adverse events.

In this interim analysis, the median progression-free survival assessed by third-party independent review was 11 months for sunitinib vs 5 months for interferon alfa. The partial response was 31% for sunitinib vs 6% for interferon alfa, with no patients experiencing a complete response. Median overall survival for patients has not been reached but will be determined as the study continues.

"The benefit [of sunitinib over interferon alfa] is demonstrated in a relatively unselected, general population of patients with metastatic renal cell carcinoma," said lead investigator Robert Motzer, MD, of the Memorial Sloan-Kettering Cancer Center, in New York City. He noted that the benefit translated across all prognostic subgroups of patients with this malignancy that the investigators studied.

"Sunitinib is the new reference standard for the first-line treatment of metastatic renal cell carcinoma," Motzer concluded. Motzer and colleagues will continue follow-up with the patients in this trial to determine the overall survival rates for individuals taking sunitinib compared with those taking interferon alfa. However, as the only long-term survivors reported to date have been treated with high-dose interleukin-2, there is still a place for first-line high-dose interleukin-2 therapy for patients who are able to tolerate its adverse effects.

TARGETING WITH TEMSIROLIMUS

Previous studies in patients with metastatic kidney cancer have also pointed to the potential for the drug temsirolimus. This agent inhibits the mammalian target of rapamycin, or mTOR, a protein involved in intracellular signaling pathways that regulate cell proliferation and survival. In a phase 2 trial, administration of this mTOR inhibitor to 111 heavily pretreated patients with advanced renal cell carcinoma resulted in a median overall survival of 15 months (Atkins MB et al. J Clin Oncol. 2004;22:909-918). Retrospectively, 49 patients were categorized in a poor-risk group (having features including high levels of low-density lipoprotein cholesterol, low hemoglobin levels, and multiple organ sites of metastasis), and the temsirolimus-treated patients in this group had a 1.7-fold longer median overall survival (from 5 months to 8.2 months) than poor-risk patients treated with first-line interferon alfa.

Preclinical animal studies revealed synergistic effects of combining temsirolimus with interferon alfa; when the agents were given alone, they only delayed tumor growth, but when combined, they resulted in tumor regression. Therefore, in this phase 3 study, patients with advanced renal cell carcinoma with poor-risk features and no prior systemic therapy were randomly assigned to one of 3 groups. One group received subcutaneous interferon alfa 3 times weekly, a second group received intravenous temsirolimus once per week, and a third group received both drugs (administered on the same schedule but at lower doses to limit toxicity).

A total of 626 patients were enrolled from July 2003 to April 2005; an interim analysis was performed in March 2006 after 442 deaths were observed. The number of deaths was similar in all 3 groups (32% to 34% of patients), but median overall survival was 7.3 months, 10.9 months, and 8.4 months in the interferon alfa, temsirolimus, and combined temsirolimus plus interferon alfa groups, respectively. Compared with interferon alfa alone, treatment with temsirolimus alone resulted in a 49% improvement in median overall survival.

"This study demonstrates the first statistically significant survival advantage for a new agent in metastatic renal cell carcinoma," said lead investigator Gary Hudes, MD, of Fox Chase Cancer Center, in Philadelphia.

There was also a statistically significant improvement in median progression-free survival for both the temsirolimus alone group (3.7 months) and the combination group (3.7 months) compared with interferon alfa alone group (1.9 months).

The most frequently occurring adverse events grade 3 or greater—weakness and fatigue, anemia, and shortness of breath—were observed in all 3 groups.

Hudes stated that temsirolimus (25 mg given intravenously each week) can be considered standard first-line therapy for patients with metastatic renal cell carcinoma and poor-risk features. "The results of this global phase 3 trial demonstrate that mTOR is an important therapeutic target in renal cell carcinoma," he added.

NEW OPTIONS FOR PATIENTS

Atkins said the results of sunitinib and temsirolimus trials will prompt changes in the treatment of renal cancer. "Sunitinib is indeed a new reference standard for first-line renal cancer therapy and temsirolimus is the first new agent to significantly prolong overall survival," he said, noting the results are likely to lead to more treatment options for patients.

While activity of these new agents was robust, however, "all is not completely rosy," Atkins added. Few if any patients experience complete responses; continued treatment seems to be required to maintain efficacy; and disease resistance usually developed within 6 to 12 months, he said. In addition, survival benefit for sunitinib has not been established; for temsirolimus, survival benefit, established only in a subset of patients with the most aggressive tumors, was just 3.5 months.

Other studies of new agents for treating kidney cancer were presented, including a phase 3 trial of the drug lapatinib, which targets the endothelial growth factor receptor (EGFR) and ERBB2. More than 400 patients with advanced renal cell carcinoma for whom first-line cytokine therapy had failed were given oral lapatinib or hormone therapy for a median of 12 weeks. While time to progression was similar with both therapies, within a subgroup of 241 patients with tumors that produced excess amounts of EGFR, median time to progression was 15.1 weeks for lapatinib vs 10.9 weeks for hormone therapy (a difference that was not statistically significant) and median overall survival was 46.0 weeks for lapatinib vs 37.9 weeks for hormone therapy, a survival benefit that was statistically significant.

Whether the drug has potential for treating patients' kidney cancers that overproduce EGFR will require additional trials. "The data thus far are hypothesis-generating, require a prospective trial, and can only be confirmed when we understand that the groups . . . were well-balanced," said Robert Figlin, MD, of the David Geffen School of Medicine at the University of California, Los Angeles.

The drugs sorafenib and bevacizumab are also being studied for the treatment of patients with advanced renal cell carcinoma. A previous trial of sorafenib (approved by the Food and Drug Administration in December for advanced renal cell carcinoma) showed that patients taking this inhibitor of Raf kinase (a protein involved in activating multiple growth factors that are aberrantly produced in various cancers) and VEGFR had a median progression-free survival of 24 weeks compared with 6 weeks for those taking placebo (Ratain MJ et al. J Clin Oncol. 2006;24:2505-2512). And in a trial of the VEGF–targeting drug bevacizumab (approved in 2004 for metastatic colorectal cancer), 64% of patients given bevacizumab were progression-free at 4 months compared with 20% of those given placebo; 30% of those in the bevacizumab group had no progression of disease at 8 months compared with 5% of those taking placebo (Yang et al. N Engl J Med. 2003;349:427-434). Several groups continue to study these targeted therapies for their effects on renal cell carcinoma.