• AVF0780g: In combination with bolus 5-fluorouracil/ folinic acid (5-FU/FA) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen).

• AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment.

Two additional trials were conducted in first (NO16966) and second line (E3200) treatment of metastatic carcinoma of the colon or rectum, with Avastin administered in the following dosing regimens, in combination with FOLFOX-4 (5FU/LV/Oxaliplatin) and XELOX (Capecitabine/Oxaliplatin):

• NO16966: Avastin 7.5 mg/kg of body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or Avastin 5 mg/kg every 2 weeks in combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).

• E3200: Avastin 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).

AVF2107g
This was a phase III randomised, double-blind, active-controlled clinical trial eva luating Avastin in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eight hundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or IFL + Avastin (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/FA+Avastin (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of Avastin with the IFL regimen was established and considered acceptable. All treatments were continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior radiotherapy and 28.4% prior chemotherapy.
The primary efficacy variable of the trial was overall survival. The addition of Avastin to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 3). The clinical benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved and duration of metastatic disease.
The efficacy results of Avastin in combination with IFL-chemotherapy are displayed in Table 3.
Table 3 Efficacy results for trial AVF2107g

  AVF2107g
 
Arm 1

IFL + placebo
 Arm 2

IFL + Avastina
 
Number of patients
 411
 402
 
Overall survival
 
Median time (months)
 15.6
 20.3
 
95% Confidence interval
 14.29 – 16.99
 18.46 – 24.18
 
Hazard ratiob
 0.660

(p-value = 0.00004)
 
Progression-free survival
 
Median time (months)
 6.2
 10.6
 
Hazard ratio
 0.54

(p-value< 0.0001)
 
Overall response rate
 
Rate (%)
 34.8
 44.8
 
  (p-value = 0.0036)

a 5 mg/kg every 2 weeks.

b Relative to control arm.

Among the 110 patients randomised to Arm 3 (5-FU/FA + Avastin) prior to discontinuation of this a