Bevacizumab-Interferon Duo Improves Progression-Free Survival in Kidney Cancer

By Charles Bankhead
VILLEJUIF, France, Dec. 20 -- When bevacizumab (Avastin) is added to interferon, the combo significantly improves progression-free survival in advanced renal cell carcinoma, investigators here reported.
The combination therapy doubled the duration of progression-free survival compared with interferon alone, Bernard Escudier, M.D., of Gustave Roussy Institute, and colleagues reported in the Dec. 22 issue of The Lancet. The frequency, severity, and mortality of adverse events did not differ between patients treated with interferon alone or interferon plus bevacizumab.
"The data presented here raise intriguing questions regarding the future of therapy for metastatic renal cell carcinoma," the authors said. "The availability of a variety of active agents provides increased treatment options and the opportunity to provide several lines of therapy and improved survival."
Metastatic renal cell carcinoma is resistant to conventional therapy. Until recently, standard systemic therapy consisted of interleukin-2 or interferon, both of which produced modest response rates at a price of substantial toxicity.
More recently, the tyrosine kinase inhibitors sorafenib and sunitinib have been approved for treatment of metastatic renal cell carcinoma. Both have been shown to improve progression-free survival in patients whose disease did not respond to interferon or IL-2, the authors noted. However, only the mammalian target of rapamycin inhibitor temsirolimus has improved overall survival compared with interferon alone.
In preliminary studies in advanced renal cell carcinoma, bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor, improved progression-free survival and time to progression, and induced durable responses lasting three to five years in some patients.
Dr. Escudier and colleagues reported findings from a randomized, double-blind phase III trial involving 649 patients with untreated metastatic disease. The patients were randomized to interferon alfa-2a (9 MIU subcutaneous three times a week) plus bevacizumab (10 mg/kg every two weeks) or interferon alfa-2a and placebo.
The primary endpoint was overall survival, and secondary endpoints included progression-free survival and safety. At a planned interim analysis, investigators changed the primary endpoint to progression-free survival, acknowledging that new second-line therapies that had become available during the trial could confound the results.
At the time of unblinding. 230 of 325 patients on combination therapy had progressed, as had 275 of 316 in the interferon-placebo group. Additionally, 114 deaths had occurred in the bevacizumab arm and 137 in the placebo arm.
Median duration of progression-free survival was 10.2 months with bevacizumab versus 5.4 months with placebo (P=0.0001).
"Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received," the authors reported.
The most common grade 3+ adverse events were fatigue (12% with bevacizumab versus 25% with placebo) and asthenia (10% with bevacizumab and 7% with placebo). Adverse event-related mortality was 2% in each treatment arm.
In a commentary that accompanied the article, Robert J. Motzer, M.D., and Ethan Basch, M.D., of Memorial Sloan-Kettering Cancer Center in New York, noted that response to therapy was assessed by individual investigators. "Lack of independent review of response might have affected the proportion of patients with reported responses, and therefore affected perceived progression-free survival outcomes."
Dr. Escudier disclosed consulting fees and honoraria from Roche, Bayer, Wyeth, Pfizer, Inate, and Antigenics. Dr. Motzer disclosed honoraria from Bayer/Onyx, current research funding from Genentech, Wyeth Research, Pfizer, and Novartis, and past research funding from Roche and Schering-Plough.
Primary source: The LancetSource reference:Escudier B, et al "Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial" Lancet 2007; 370: 2103-2111. Additional source: The LancetSource reference: Motzer R, Basch E, "Targeted drugs for metastatic renal cell carcinoma" Lancet 2007; 370: 2071-2073.