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Bevacizumab added to interferon-alpha as initial systemic therapy for metastatic renal cell carcinoma did not significantly improve overall survival compared to interferon alone, but did significantly increase progression-free survival.
The multicenter study, presented at the American Society of Clinical Oncology annual meeting, included 732 patients with confirmed metastatic RCC with a component of clear cell histology who were randomized to interferon-alpha, 9 MU/m2 three times weekly, or interferon-alpha at the same dosing schedule plus bevacizumab, 10 mg/kg intravenously on days 1 and 15.
Patients were stratified by the absence or presence of prior nephrectomy and by their Memorial Sloan-Kettering Cancer Center (MSKCC) risk score (favorable, intermediate, or poor risk) that was developed for patients receiving interferon-based therapies.
Twenty-six percent of the patients in each arm had a favorable risk score (zero adverse risk factors), 64% were intermediate risk (one or two adverse risk factors), and 10% were poor risk (three or more adverse risk factors).
The median overall survival was 18.3 months in patients initially randomized to bevacizumab and interferon-alpha compared to 17.4 months in those initially randomized to interferon-alpha alone; this difference failed to achieve statistical significance (stratified log-rank p=.069).
Mean overall survival analyzed by MSKCC risk group criteria revealed a relatively consistent but nonsignificant improvement in patients assigned to bevacizumab plus interferon-alpha.
During the course of the trial, several other active therapies, including vascular endothelial growth factor (VEGF)-targeted therapies, emerged.
"Therefore, the vast majority of patients who were initially entered into this study received subsequent therapy," said first author Brian I. Rini, MD, associate professor, department of solid tumor oncology and urology, Cleveland Clinic Taussig Cancer Center. "Approximately 56% overall received at least one subsequent systemic therapy."
Sixty-two percent of patients initially randomized to interferon-alpha alone received subsequent therapy. Of those assigned to interferon-alpha alone who received subsequent systemic therapy, 46% received VEGF-targeted therapy (ie, sunitinib [Sutent], sorafenib [Nexavar]) and 14% received bevacizumab.
The median overall survival in both treatment arms was exceedingly long compared to historical controls, said Dr. Rini. The assumption when the study was designed was that the addition of bevacizumab to interferon-alpha would increase median overall survival from 13 months to 17 months. In the 408 patients overall who were well enough to receive second-line therapy after progression, the median overall survival was 31.4 months in patients assigned to initial therapy with bevacizumab/interferon-alpha and 26.8 months in those assigned to initial therapy with interferon-alpha alone.
"The treatment effect with initial bevacizumab and interferon was maintained regardless of receiving second-line therapy," he said.
Median progression-free survival was 8.4 months in the bevacizumab/interferon-alpha arm vs. 4.9 months in the interferon-alpha arm (hazard ratio: 0.71; p<.0001). The objective overall response rate was 25.5% and 13.1% (p<.0001) in the treatment groups, respectively. (The superiority of bevacizumab/interferon-alpha over interferon-alpha alone on progression-free survival and the objective response rate had been demonstrated previously in phase III studies.)
Grade 3/4 adverse events occurred in 79% of patients assigned to initial bevacizumab/interferon-alpha and 61% assigned to interferon-alpha monotherapy. Proteinuria was present in 15% receiving bevacizumab as initial therapy compared to less than 1% randomized to initial interferon-alpha, and the incidence of hypertension was 11% in the bevacizumab/interferon-alpha group and 0% in the group randomized interferon-alpha alone. There was no significant difference in the incidence of hemorrhage, venous thromboembolism, gastrointestinal perforation, and arterial ischemia between the two groups.
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NEWS & UPDATE
The FDA has approved pazopanib (Votrient) for the treatment of advanced renal cell carcinoma. See: http://www.urologytimes.com/pazopanib/