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Bevacizumab in combination with interferon-a nearly doubled survival in patients with metastatic renal cell carcinoma in a phase III trial. Comparative studies are needed, but the results suggest that "this combination is a good automatic first-line treatment," lead author Dr. Bernard Escudier said at a press briefing.
The results could breathe new life into the use of interferon and provide an alternative to current options, including the recently approved antiangiogenic agent, sunitinib malate (Sutent). The combination treatment may also offer a safety advantage.
"Safety is going to be a little in favor of this combination," said Dr. Escudier, head of the immunotherapy and innovative therapy unit at the Institut de cancérology Gustave Roussy, Villejuif, France. "In this study, patients received interferon for 1 year, then stopped interferon and continued on bevacizumab [Avastin] alone, which is a very safe way to give treatment to patients, compared [with] continuing on interferon for a very long time."
An interim analysis of overall survival after 251 deaths was convincing enough that the multinational trial, known as the AVOREN study, was unblinded early and patients in the interferon plus placebo arm were offered treatment with bevacizumab.
In all, 649 nephrectomized patients with clear cell metastasized renal cell carcinoma were randomized to interferon-a-2a (IFN-a-2a) three times a week at the recommended dose of 9 million IU for up to 1 year, plus bevacizumab 10 mg/kg twice weekly or placebo until disease progression. A total of 641 patients received treatment, and 595 were available for analysis.
The overall response rate was 31% among 306 patients who received IFN-a-2a plus bevacizumab, compared with 13% among 289 patients who received IFN-a-2a plus placebo. Complete response was observed in 1% of IFN-a-2a/bevacizumab patients and in 2% of IFN-a-2a/placebo patients. Partial response was reported in 30% and 11%, respectively. Median duration of response was 13 and 11 months, respectively. Some tumor shrinkage was reported in significantly more patients treated with IFN-a-2a/bevacizumab than in patients treated with IFN-a-2a/placebo (70% vs. 39%).
The addition of bevacizumab to interferon was associated with significantly longer median progression-free survival (PFS): 10.2 months, compared with 5.4 months for IFN-a-2a plus placebo (P less than .004). The hazard ratio was 0.60, Dr. Escudier reported.
When the data were stratified by Motzer risk category, PFS was significantly better among intermediate-risk patients treated with bevacizumab, compared with interferon alone (10.2 months vs. 4.5 months, P less than .0001). Previous research by Dr. Escudier indicated that interferon has little, if any, activity among these patients, he said, suggesting the response is probably mainly caused by bevacizumab.
No significant difference in PFS was observed among Motzer poor-risk patients (2.2 months vs. 2.1 months).
The data are compelling enough to suggest adding the bevacizumab/interferon combination as a treatment option for good- or intermediate-risk patients who are treatment naive, discussant Dr. Ronald Bukowski, director of experimental therapeutics at Cleveland Clinic, said during the formal presentation of the data at a plenary session.
"It seems reasonable to me to ask whether a cytokine in this combination is necessary or whether bevacizumab monotherapy, potentially which tends to be less toxic, would be equally as effective," Dr. Bukowski said. He also called for a three-arm trial comparing sunitinib monotherapy, sunitinib plus bevacizumab, and bevacizumab plus interferon.
Although both sunitinib and bevacizumab target the angiogenic vascular endothelial growth factor (VEGF), the two drugs have different key mechanisms of action. Bevacizumab is a humanized monoclonal antibody that blocks circulating VEGF, whereas sunitinib is a tyrosine kinase inhibitor that blocks the VEGF receptor and other receptors, Dr. Escudier explained in an interview. Sunitinib "has a wider activity, but also probably a wider toxicity because it's blocking many receptors."
No new toxicities emerged in the study beyond those known to be associated with interferon and bevacizumab. There were 137 grade 3/4 adverse events in the IFN/placebo arm vs. 203 in the bevacizumab/IFN arm. Reports of fatigue, asthenia, and malaise were more common with bevacizumab than placebo (76 vs. 46 events), possibly because of the longer duration of treatment, Dr. Escudier said.
Roche has filed for approval of bevacizumab as a first-line treatment for renal cell carcinoma in the European Union, while Genentech Inc. is expected to file in the United States in the near future, he said.
Escudier B. et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-a2a vs. placebo/interferon-a2a as first-line therapy in metastatic renal cell carcinoma. Abstract 3.
Commentary |
The AVOREN study—a multinational, randomized, placebo-controlled phase III trial of interferon-a-2a (IFN-a-2a) plus bevacizumab vs. INF-a-2a and placebo—revealed a dramatic improvement in the time to disease progression in favor of the bevacizumab-treated patients with metastatic renal cell carcinoma. The addition of bevacizumab to INF-a-2a was associated with significantly longer median progression-free survival, greater overall response, and longer median response. In addition, there was a trend toward improved survival in favor of the bevacizumab-treated patients (median survival not reached vs. 19.8 months, P = .0267; hazard ratio = 0.75), which did not reach the prespecified level of significance for this interim analysis (P = .0056). Toxicity also was significantly different between the two arms. Grade 3 or 4 adverse events occurred more frequently with IFN-a-2a plus bevacizumab, compared with the control group (60% vs. 45%). There was a higher incidence of grade 3 or 4 fatigue (23% vs. 15%), proteinuria (6.5% vs. 0%), hypertension (3.9% vs. 0.7%), hemorrhage (3.3% vs. 0.3%), thromboembolic event (1.8% vs. 0.7%), gastrointestinal perforation (1.5% vs. 0%), and arterial ischemic event (1.2% vs. 0.3%). The current FDA-approved standard of care for patients with metastatic renal cell cancer is treatment with a multitargeted kinase inhibitor such as sunitinib (Sutent) or sorafenib (Nexavar); temsirolimus (Torisel), an intravenously administered mTOR inhibitor; or high-dose interleukin-2 (IL-2, Proleukin) therapy in selected patients. The AVOREN study reported clinical results comparable to other first-line treatments. In particular, the first-line phase III trial comparing sunitinib to IFN-a-2a showed a similar difference in progression-free survival (11 months vs. 4 months, P less than .001) and overall response rate (44% for sunitinib vs. 11%, P = less than .001). The toxicity reported in patients treated with IFN-a-2a plus bevacizumab is concerning, however. In particular, 28% of patients discontinued treatment due to toxicity in the IFN-a-2a plus bevacizumab arm vs. only 12% in the IFN-a-2a alone arm. By comparison, in the first-line sunitinib vs. IFN-a-2a study, only 8% of patients discontinued sunitinib due to toxicity vs. 11% of IFN-a-2a treated patients. These differences in tolerability make the IFN-a-2a plus bevacizumab less compelling. It will be critical to determine how much of the clinical benefit seen with this combination is due to bevacizumab. Prior studies of bevacizumab alone or in combination with other targeted therapies reveal a time to disease progression from 8 to 11 months. Future studies that evaluate regimens containing bevacizumab are needed to determine the optimal integration of this therapy into the treatment of metastatic kidney cancer. — Daniel J. George, M.D. and Judd W. Moul, M.D.
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