Bevacizumab used in combination with interferon alfa as a first-line treatment for metastatic renal cell carcinoma (RCC) nearly doubled progression-free survival in patients taking part in an international phase III trial.
The randomized, double-blind study of more than 600 adults who had received no prior treatment for the condition showed the combination therapy to be significantly more effective than interferon alfa alone, increasing the median duration of progression-free survival from 5.4 months to 10.2 months.
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In reporting the results of their trial in the Lancet (2007;370:2103-2111), Bernard Escudier, MD, of Institut Gustave Roussy in Villejuif, France, and colleagues noted that the standard treatment for metastatic RCC—immunotherapy with interleukin 2 or interferon—usually produces overall response rates of less than 20%, as well as substantial toxicities.
Because vascular endothelial growth factor (VEGF) inhibition is a valid treatment approach for this type of cancer, the investigators wanted to determine the effectiveness of bevacizumab (Avastin), an anti-VEGF monoclonal antibody, when used with interferon alfa. In phase II studies, bevacizumab alone resulted in a median progression-free survival of 8.5 months in previously untreated patients. In those who had been treated previously, bevacizumab alone increased the median time to disease progression to 4.8 months compared with 2.5 months for placebo.
Between June 2004 and October 2005, 649 patients in several European countries were assigned to receive either bevacizumab plus interferon alfa-2a (327 patients; median age 61 years [range 30-82 years]) or placebo plus interferon alfa (322 patients; median age 60 years [18-81 years]). The participants had measurable or non-measurable tumor; predominantly clear-cell RCC; and normal hepatic, hematopoietic, and renal function with no more than minimal proteinuria (0.5 g of protein or less every 24 hours) at baseline.
Patients received 10 mg/kg of bevacizumab or placebo IV every two weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Interferon alfa-2a was injected subcutaneously at a recommended dose of 9 MIU (reduced in some patients to 3 or 6 MIU) three times per week for no more than 52 weeks or until disease progression, unacceptable toxicity, or withdrawal of consent. The clinical data cutoff point was reached in September 2006, when 251 (56%) of the 445 deaths required to adequately perform the final analysis of overall survival—the primary end point of the trial—had occurred.
Two patients in the bevacizumab group and six patients in the control group withdrew from the study before treatment, the investigators reported. In the bevacizumab group, median treatment duration was nearly twice as long compared with the control group (9.7 months vs. 5.1 months).
Clinical outcomes
In addition to the near-doubling of median progression-free survival, the bevacizumab group had
a significantly higher overall response rate, with 214 (70%) bevacizumab patients experiencing tumor shrinkage compared with 112 (39%) of the control patients. The bevacizumab group also had a longer median duration of response (13.5 months vs. 11.1 months) and a longer median duration of stable disease (10.1 months vs. 7.2 months).
Safety profile
According to the researchers, “the safety profile of the combination of bevacizumab and interferon alfa was consistent with toxicities seen with each of these agents; grade 3/4 events were manageable with standard therapies.”
Serious adverse events occurred in 98 bevacizumab patients (29%) and 50 of the other patients (16%). A greater proportion of the bevacizumab group had to stop treatment due to an adverse event, according to investigators. The most commonly reported serious adverse events in both groups were fatigue, asthenia, neutropenia, and other established interferon-related toxicities.
