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

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2007

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Presenter: Bernard Escudier
Presenter's Affiliation: Institut Gustave Roussy, Villejuif, France
Type of Session: Plenary

Background

  • Until recently, treatment of metastatic renal cell carcinoma (RCC) included immunotherapy as the standard of care.
  • Treatment with interferon (IFN) provided modest clinical benefit and toxicity with an expected median progression free survival of 4.7 months and median overall survival of 13-14 months.
  • VEGF has become a critical target in this disease and agents that target this pathway have recently been approved.
  • The bevacizumab dose of 10mg/kg q2w has shown an acceptable safety profile as monotherapy in RCC.
  • Two phase II clinical trials have shown improved progression free survival in patients treated with bevacizumab for RCC.

Materials and Methods

  • This was a randomized, multinational, double-blinded phase III study.
  • 649 patients with metastatic RCC were enrolled.
  • Patients were randomized to either interferon-a2a and placebo or interferon-a2a + bevacizumab.
  • The interferon dose was 9MIU given subcutaneously three times a week for a maximum of 52 weeks.
  • Bevacizumab was given as 10mg/kg IV q 2 weeks until disease progression.
  • Patients were stratified by country and Motzer score.
  • The primary endpoint was overall survival.
  • Secondary endpoints included progression free survival, time to disease progression, time to treatment failure and objective response rates.
  • Toxicities and pharmacokinetics were studied as well.
  • Patients could be enrolled if they had confirmed metastatic RCC with at least 50% clear cell histology, a nephrectomy, and Karnofsky status of >70%.
  • Patients were excluded for any prior systemic treatment for metastatic RCC, evidence of current CNS metastases or spinal cord compression, evidence of bleeding diathesis or coagulopathy, or use of full therapeutic doses of oral or parenteral anticoagulants.
  • Patients were well balanced in terms of patient related and disease specific prognosticators.

Results

  • The overall response rate by investigator assessment was significantly higher in the bevacizumab arm (31% vs. 13%).
  • Progression free survival by investigator assessment was significantly improved in the bevacizumab arm (HR 0.63, p<0.0001).
  • The bevacizumab arm had improved median progression free survival compared to the placebo arm (10.2 months vs. 5.4 months, p<0.0001).
  • The improvement in progression free survival was seen in both the favorable prognosis subgroup patients (median PFS 12.9 months vs. 7.6 months, p=0.004) and the intermediate prognosis subgroup patients (median PFS 10.2 months vs. 4.5 months, p<0.0001).
  • There was no difference seen between the arms for the unfavorable prognosis subgroup patients (median 2.2 vs. 2.1 months, p = NS).
  • Interim analysis of overall survival was presented and appears improved in the bevacizumab arm (HR 0.75, p<0.0267).
  • The final overall survival analysis may be confounded by the large numbers of patients who have already received second line therapy (39% in the placebo arm and 28% of the bevacizumab arm)
  • Median duration of treatment was higher in bevacizumab arm (10 months vs. 5 months) and patients on the experimental arm received more interferon as well.
  • Grade >3 adverse events were seen in 60% of the bevacizumab patients and 45% of the placebo arm.
  • There were 2 treatment related deaths in both arms.
  • The bevacizumab patients had higher rates of grade 3 or 4 toxicities including: hypertension (3.9 % vs. 0.7%), hemorrhage (3.3% vs. 0.3%), venous thromboembolism (1.8% vs. 0.7%) and arterial ischemia (1.2% vs. 0.3%).

Author's Conclusions

  • The addition of bevacizumab to IFN results in clinically important and statistically significant improvements in progression free survival and tumor response.
  • There is a trend in favor of improved overall survival.
  • The treatments were well tolerated and no new toxicities emerged outside of those known with IFN and bevacizumab.

Clinical/Scientific Implications

This study was a well designed and executed phase III randomized trial. There have been a number of recent phase III trials for this disease presented at the ASCO meeting using a variety of novel agents (sunitinib, temsirolimus, sorafenib). Remarkably, each one of the trials reported positive results. One criticism of this trial is that using interferon as monotherapy would not be expected to provide much of a benefit. Thus, based on this trial, we do not understand how important the relative activities of bevacizumab and interferon really and it is difficult to compare these results to the other recent trials showing activity. However, the authors' conclusions are valid. The addition of bevacizumab does in fact appear to provide a clinically important benefits in this disease. It would be interesting to perform a randomized trial comparing this regimen to other active regimens that have been making headlines over the last few years.


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