AVADO — Final Overall Survival Results of First-Line Docetaxel in Combination with Escalating Doses of Bevacizumab for HER2-Negative Metastatic Breast Cancer

DR BRUFSKY: The background for this analysis presented by Miles and colleagues is provided by three trials that reported positive disease-free survival results with first-line bevacizumab on their initial analyses. ECOG-E2100, RIBBON 1 and AVADO all demonstrated that bevacizumab combined with first-line chemotherapy for patients with metastatic breast cancer improves progression-free survival.

This presentation by Dr Miles reported the final, preplanned overall survival analysis at 25 months of the AVADO trial, which evaluated docetaxel in combination with placebo versus docetaxel in combination with two escalating doses of bevacizumab. Patients received treatment until disease progression.

The bottom line in this particular trial was that a substantial increase in progression-free survival was reported with the addition of bevacizumab, particularly the 15-mg dose, with no unexpected toxicity. One of the main complaints about AVADO when it was first reported at ASCO 2008 was that the trial reported a minimal progression-free survival benefit. But these updated results, particularly with the 15-mg/kg dose, are substantial — 10 months versus 8.1 months — and highly statistically significant.

An 18 percent improvement in response rate was also seen — it increased from 46 percent to about 64 percent. But there was no difference in the primary overall survival endpoint at 25 months, which is similar to reports from ECOG-E2100 and RIBBON 1. These trials show a substantial effect, a positive benefit for treatment of patients with metastatic breast cancer with bevacizumab. I believe the take-home message from this trial is that you can feel fairly comfortable administering bevacizumab with docetaxel. These results combined with RIBBON 2 in the second-line setting indicate that taxanes and bevacizumab are a good match.

DR LOVE: Do you think that the lack of a survival benefit might have something to do with the duration of bevacizumab administration?

DR BRUFSKY: I think that’s going to be the answer at the end of the day. Current basic and translational literature have reported in animal models that when you stop administering bevacizumab, or any anti-angiogenic agent for that matter, you get a rebound effect where you actually get more tumor growth when you discontinue the agent.

I think bevacizumab is a drug that’s going to need to be used continuously to provide benefit. Many of us who have been involved in these trials are interested in conducting a new study that would be called the RIBBON 3 trial, in which patients go on bevacizumab and are then randomly assigned to stop the bevacizumab at first disease progression or continue through multiple lines. I believe that’s the only way we’re going to answer this question, which was also raised in evaluating the adjuvant colon data with bevacizumab.

Dr Brufsky is Associate Professor of Medicine and Associate Division Chief of Hematology/Oncology at the University of Pittsburgh, Co-Director of the Comprehensive Breast Cancer Center and Associate Director for Clinical Investigation at the University of Pittsburgh Cancer Institute in Pittsburgh, Pennsylvania.