(p-value = 0.0062)
 
Progression-Free Survival
  
Median (months)
 4.1
 5.7
 
Hazard ratio (95% confidence interval)
 0.68 (0.59, 0.78)

(p-value < 0.0001)
 
Objective Response Rate (ORR)
  
Patients included in analysis
 406
 404
 
Rate
 3.9%
 5.4%
 
  (p-value = 0.3113)
 

a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks

Statistically significant improvements in progression-free survival were also observed. Objective response rate was low in both treatment arms and the difference was not significant.

Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients, while study ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-pretreated patients. A cross-trial comparison of the efficacy and safety data is limited by differences between these studies, most notably in patient populations, previous bevacizumab exposure and chemotherapy regimens. Both the 5 mg/kg/week and 2.5 mg/kg/week equivalent doses of bevacizumab provided a statistically significant benefit with regards to OS (HR 0.751 in study E3200; HR 0.81 in study ML18147) and PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of safety, there was a higher overall incidence of Grade 3-5 AEs in study E3200 relative to study ML18147.

Metastatic breast cancer (mBC)

Two large Phase III trials were designed to investigate the treatment effect of Avastin in combination with two individual chemotherapy agents, as measured by the primary endpoint of PFS. A clinically meaningful and statistically significant improvement in PFS was observed in both trials.

Summarised below are PFS results for the individual chemotherapy agents included in the indication:

• Study E2100 (paclitaxel)
 
  • Median PFS increase 5.6 months, HR 0.421 (p < 0.0001, 95% CI 0.343; 0.516)
 
• Study AVF3694g (capecitabine)
 
  • Median PFS increase 2.9 months, HR 0.69 (p = 0.0002, 95% CI 0.56; 0.84)
 

Further details of each study and the results are provided below.

ECOG E2100

Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial eva luating Avastin in combination with paclitaxel for locally recurrent or metastatic breast cancer in patients who had not previously received chemotherapy for locally recurrent and metastatic disease. Patients were randomised to paclitaxel alone (90 mg/m2 IV over 1 hour once weekly for three out of four weeks) or in combination with Avastin (10 mg/kg IV infusion every two weeks). Prior hormonal therapy for the treatment of metastatic disease was allowed. Adjuvant taxane therapy was allowed only if it was completed at least 12 months prior to trial entry. Of the 722 patients in the trial, the majority of patients had HER2-negative disease (90%), with a small number of patients with unknown (8%) or confirmed HER2-positive status (2%), who had previously been treated with or were considered unsuitable for trastuzumab therapy. Furthermore, 65% of patients had received adjuvant chemotherapy including 19% prior taxanes and 49% prior anthracyclines. Patients with central nervous system metastases, including previously treated or resected brain lesions, were excluded.

In trial