Randomised, double-blind, placebo controlled, phase III study of bevacizumab (BV) with docetaxel (D) or docetaxel with placebo (PL) as first line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 1 de junio del 2008

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Presenter: David Miles, MD
Presenter's Affiliation: Mount Vernon Cancer Center, UK
Type of Session: Scientific

Background

  • Bevacizumab (BV) is a monoclonal antibody to VEGF that inhibits angiogenenesis, and therefore prevents tumor growth. It has been studied in multiple clinical trials in combination with other agents for various tumor types in the metastatic setting. BV has been shown to improve OS and PFS in these previous studies.  
  • The E2100 trial, a phase III trial of weekly paclitaxel versus weekly paclitaxel/bevacizumab for metastatic breast cancer, by K. Miller, et al. demonstrated that the combination of BV and paclitaxel led to an improvement in response rate (RR) and progression free-survival (PFS).
  • The current AVADO study was undertaken to examine the hypothesis that the addition of BV will also improve PFS in patients treated with docetaxel, as opposed to paclitaxel, as first line therapy in patients with locally recurrent or metastatic breast cancer.
  • This study was performed in Europe, where docetaxel is more commonly administered than paclitaxel, and therefore it was necessary to determine whether the results of the E2100 study can be clinically relevant for patients who receive docetaxel for MBC as well. 

Materials and Methods

  • This is a double-blind, placebo controlled phase III study. Patients were randomized to one of 3 arms: 
    • docetaxel + placebo (D+PL) = D at 100 mg/m2 + PL q 3 weeks  
    • docetaxel + low dose BV (D+BV1) = same dose D + BV at 7.5 mg/kg q 3 weeks 
    • docetaxel + high dose BV (D+BV2)= same dose D + BV at 15 mg/kg q 3 weeks.
  • Comparisons were performed between the placebo group and each BV group; however, the 2 BV groups were not compared directly. 
  • Docetaxel was administered q3 weeks for up to 9 cycles. BV/PL was administered until disease progression or limiting toxicity. 
  • The primary endpoint studied was PFS. Secondary endpoints included overall survival (OS), time to treatment failure (TTF), duration of response and safety.
  • Eligibility criteria included women >18 years, ECOG PS 0-1, Her2 negative status, and no prior chemotherapy for metastatic disease. 
  • Prior adjuvant chemotherapy was allowed if relapse > 6 months ago (> 12 months if prior taxane therapy was used for adjuvant chemotherapy). The study used an 80% power for a 2-sided unstratified long-rank test to detect differences in PFS with hazard ratio of 0.7. Based on this,   705 patients were required for this study. 

Results

  • Between March 2006 and April 2007, 736 patients at 104 sites in 24 countries were randomized. The median follow up was 10.2 months (range 0-17.5 months). There were no significant patient characteristic differences noted between the 2 groups, except that the BV arms had a slightly higher percentage of more than 3 metastatic sites. Two-thirds of patients had received adjuvant chemotherapy prior to this trial: 50% antracyclines and 15% taxanes. 
  • PFS was statistically significantly improved for both BV dose groups compared to the placebo groups. 
    • In an unstratified analysis, median PFS for the D+PL group compared to the D+BV1 group was 8 mos. vs. 8.7 mos. respectively. This was statistically significant with a HR of 0.79 (p=0.03). Median PFS for the D+PL group compared to the D+BV2 group was 8 mos. vs. 8.8 mos. respectively. This was also statistically significant with a HR of 0.72 (p=0.01). 
    • In a stratified analysis (by criteria at study entry: not mentioned by authors), both BV groups, D +BV1 and D+BV2, had increased PFS compared to D+PL, with hazard ratios of 0.69 and 0.61, respectively (p<0.0001). 
    • Subgroup analyses were not reported since subgroups were not powered to detect differences.
  • Increased response rates were also seen in both BV groups compared to the control arm. Response rate (RR) (defined as % of CR+PR) was 44 % for arm 1, 55% for arm 2, and 63% for arm 3. These results were statistically significantly different with p=0.0295 and p=0.0001 betweens arms 1 and 2 and arms 1 and 3, respectively.
  • The authors did not report OS data as the study is too immature to provide meaningful results. 
  • Although there was no excess in grade 4 or 5 toxicity in the BV arms, grade 3 adverse events were higher in the BV arms compared to the placebo arm. 8.9% of patients in arm 2 and 11.7% of patients in arm 3 discontinued treatment secondary to toxicity. There was no difference seen in HTN, GI perforation, or thromoembolic events between the various arms. The incidence of febrile neutropenia was increased in the BV arms compared to the placebo arm; however, anemia and infection rates were higher in the control group. 

Author's Conclusions

  • This study demonstrates a clinical benefit in PFS and RR for the combination of bevacizumab and docetaxel as a 1st line treatment for metastatic breast cancer patients. 
  • This benefit was seen for both doses of BV used in this trial. 
  • The addition of BV added limited toxicity relative to the control group; however, no serious adverse events (grade 4 or 5) were reported. Safety data was comparable for the 2 BV arms as well. 

 

Clinical/Scientific Implications

  • Taxanes, such as paclitaxel and docetaxel, have emerged in the last 10 years as fundamental drugs in the treatment of breast cancer. Their benefits were first shown in the metastatic setting. Although taxanes are effective drugs, new targeted therapies to further improve survival and prevent progression in patients with metastatic breast cancer are needed. 
    • VEGF inhibitors such as BV have been shown to improve outcomes in various tumor types in combination with standard chemotherapy. 
  • Although the E2100 study examined the combination of BV and paclitaxel and demonstrated an improved outcome with combination treatment, there have been no trials studying docetaxel. 
    • As the authors note in their conclusions, this study is the first randomized phase III trial showing a benefit of the addition on BV to docetaxel in the treatment of metastatic breast cancer.  
  • Both studies did show an increase in RR and PFS; however, there were some differences in the results between the 2 trials. The authors concluded that the addition of BV to docetaxel improved PFS, but the absolute improvement was only 0.7-0.8 months (8.0 vs. 8.7/8.8 months). The PFS improvement seen in the E2100 study was 5.9 vs. 11.8 months. 
    • It is unclear why these data differ so greatly, but some have proposed that it may due to the time intervals at which paclitaxel and docetaxel are given. In the E2100, paclitaxel is given weekly, whereas in this study, docetaxel is given q 3 weeks. One can hypothesize that since paclitaxel is given more often, there may be a “dual hit” on the tumor cells when both drugs are administered. 
    • The difference may also be related to the fact that the placebo group did better in the docetaxel study, and therefore a small absolute difference was seen.
  • This study does show a potential benefit to combining anti-angiogenic agents with taxanes for metastatic breast cancer, however further follow up is needed to make conclusions regarding overall survival. 
  • Future studies, like the ongoing RIBBON trial, should focus on evaluating the effects of adding antiangiogenic agents, such as BV, to other chemotherapeutic drugs used in metastatic breast cancer. 

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