The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial, there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that Avastin in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy alone. Both co-primary objectives were met:

• Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival and overall survival in the eligible per-protocol population.

• Superiority of the Avastin-containing arms versus the chemotherapy alone arms in the overall comparison was demonstrated in terms of progression-free survival in the ITT population (Table 7).

Secondary PFS analyses, based on 'on-treatment'-based response assessments, confirmed the significantly superior clinical benefit for patients treated with Avastin (analyses shown in Table 7), consistent with the statistically significant benefit observed in the pooled analysis.

Table 7 Key efficacy results for the superiority analysis (ITT population, trial NO16966)

Endpoint (months)
 FOLFOX-4 or XELOX + placebo

(n=701)
 FOLFOX-4 or XELOX + bevacizumab

(n=699)
 P-value
 
Primary endpoint
 
Median PFS**
 8.0
 9.4
 0.0023
 
Hazard ratio (97.5% CI) a
  0.83 (0.72-0.95)
  
Secondary endpoints
 
Median PFS (on treatment)**
 7.9
 10.4
 < 0.0001
 
Hazard ratio (97.5% CI)
 0.63 (0.52-0.75)
  
Overall response rate

(invest. assessment)**
 49.2 %
 46.5 %
  
Median overall survival*
 19.9
 21.2
 0.0769
 
Hazard ratio (97.5% CI)
 0.89 (0.76-1.03)
  

* Overall survival analysis at clinical cut-off 31 January 2007

** Primary analysis at clinical cut-off 31 January 2006

a relative to control arm

In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in bevacizumab treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the corresponding results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; p-value = 0.0026.

The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treated patients in the FOLFOX treatment subgroup, HR=0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, the corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84, 97.5% CI = [0.68; 1.04]; p-value = 0.0698.

ECOG E3200

This was a phase III randomised, active-controlled, open-label trial investigating Avastin 10 mg/kg in combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treated patients (s