til disease progression at a recommend starting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients were stratified according to country and Motzer score and the treatment arms were shown to be well balanced for the prognostic factors.
The primary endpoint was overall survival, with secondary endpoints for the trial including progression-free survival. The addition of Avastin to IFN-alpha-2a significantly increased PFS and objective tumour response rate. These results have been confirmed through an independent radiological review. However, the increase in the primary endpoint of overall survival by 2 months was not significant (HR= 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55% Avastin/IFN) received a variety of non-specified post-trial anti-cancer therapies, including antineoplastic agents, which may have impacted the analysis of overall survival.
The efficacy results are presented in Table 12.
Table 12 Efficacy results for trial BO17705
BO17705
Placebo+ IFNa
Bvb + IFNa
Number of patients
322
327
Progression-free survival
Median (months)
5.4
10.2
Hazard ratio
95% CI
0.63
0.52, 0.75
(p-value < 0.0001)
Objective response rate (%) in Patients with measurable disease
n
289
306
Response rate
12.8%
31.4%
(p-value <0.0001)
a Interferon alfa-2a 9 MIU 3x/week
b Bevacizumab 10 mg/kg q 2 wk
Overall survival
Median (months)
21.3
23.3
Hazard ratio
95% CI
0.91
0.76, 1.10
(p-value 0.3360)
An exploratory multivariate Cox regression model using backward selection indicated that the following baseline prognostic factors were strongly associated with survival independent of treatment: gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, number of metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for these baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63;0.96], p = 0.0219), indicating a 22% reduction in the risk of death for patients in the Avastin+ IFN alfa-2a arm compared to IFN alfa-2a arm.
Ninety seven (97) patients in the IFN alfa-2a arm and 131 patients in the Avastin arm reduced the dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol. Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of Avastin and IFN alfa-2a based on PFS event free rates over time, as shown by a sub-group analysis. The 131 patients in the Avastin + IFN alfa-2a arm who reduced and maintained the IFN alfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receiving Avastin + IFN alfa-2a.
AVF2938
This was a randomised, double-blind, phase II clinical trial investigating Avastin 10 mg/kg in a 2 weekly schedule with the same dose of Avastin in combination with 150 mg daily erlotinib, in patients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this trial, 53 to Avastin 10 m
