Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. (2008)

LBA1011 Background: BV (Avastin®), an anti-angiogenic monoclonal antibody that prevents the biologic activity of VEGF, significantly improves overall (OS) and/or progression-free survival (PFS) in four tumour types. In patients with mBC, the phase III study E2100 demonstrated that BV in combination with paclitaxel as 1st-line therapy resulted in superior PFS compared with paclitaxel alone (hazard ratio [HR] = 0.48 as per independent review).The AVADO study investigated the combination of BV and D as first-line therapy in patients with locally recurrent or mBC. Methods: This randomised, double-blind phase III study compared D 100mg/m2 plus PL with D plus either BV 7.5mg/kg or BV 15mg/kg. D was administered q3w for up to 9 cycles. BV/PL was administered q3w until disease progression or unacceptable toxicity. The 1° endpoint was PFS, with 2° endpoints of OS, time to treatment failure, best overall response, duration of response, and safety. Key eligibility criteria were HER2-negative, inoperable locally recurrent or mBC; no prior chemotherapy for advanced disease; ECOG PS 0–1; adequate LVEF, and no CNS metastases. Statistical assumptions: 80% power for a 2-sided unstratified log-rank test to detect a HR for PFS of 0.7, for each BV arm compared with the PL arm (overall α=5%). Results: March 2006 to April 2007, 736 patients in 24 countries were randomised. With median follow-up of ∼11 months PFS was statistically significantly superior for both BV containing arms compared with D alone. ORR was superior in both combination arms relative to D alone. OS is immature due to short follow up. Conclusions: Both doses of BV in combination with D significantly improved PFS and RR compared with D alone. BV added limited incremental toxicity relative to control. Safety results were comparable on the two BV arms and the overall findings did not reveal any new safety signals. D + PL D + BV7.5mg/kg D + BV15mg/kg All randomised patients (n) 241 248 247 PFS Unstratified HR vs D + PL (95% CI) 0.79 (0.63, 0.98) 0.72 (0.57,0.90) p-value (log-rank test)* 0.0318 0.0099 Stratified HR vs D + PL† (95% CI) 0.69 (0.54, 0.89) 0.61 (0.48, 0.78) p-value (log-rank test)* 0.0035 0.0001 Response rate (CR + PR) (%)‡ 44.4 - 55.2 63.1 p- value vs D + PL 0.0295 0.0001 Safety population (n) 233 250 247 Grade ≥3 adverse events (%) 67.0 74.8 74.1 Grade ≥3 hypertension (%) 1.3 0.4 3.2 Grade ≥3 arterial thromboembolic events (%) 0.4 − 0.4 − 0.4 Grade ≥3 GI perforation (%) 0.9 0.8 − 16.6 Grade ≥3 CHF (%) − 12.0 15.2 Grade ≥3 febrile neutropenia (%) Any grade 5 adverse event (up to 21 days after last dose) (%) 2.6 1.6 1.6 *p-values adjusted for multiple testing †pre-specified stratifiedanalysis with censoring for additional anti-neoplastic therapy that started prior to Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche, sanofi-aventis Roche Roche, sanofi-aventis Roche Roche, sanofi-aventis