S4-8: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2−positive locally recurrent/metastatic breast cancer (LR/mBC)

Background: H + taxane is an established and effective first-line treatment for HER2−positive LR/mBC. Preclinical data provide the rationale for combining BEV and H in HER2−positive LR/mBC but clinical data in this setting are limited to single-arm phase II studies. AVEREL is the first randomized trial of BEV in HER2−positive LR/mBC. Methods: Eligible patients had measurable or evaluable HER2−positive LR/mBC (centrally confirmed IHC 3+ or FISH/CISH +), ECOG performance status 0/1, and had received no prior chemotherapy for advanced disease. Prior adjuvant H/taxanes were permitted unless disease had recurred 2 q3w) or H + DOC + BEV (15 mg/kg q3w). H and BEV were given until disease progression; DOC was given for a planned minimum of 6 cycles unless progression or unacceptable toxicity mandated earlier discontinuation. The primary endpoint was progression-free survival (PFS). Additional endpoints included overall survival (OS), overall response rate (ORR; assessed by RECIST 1.0), duration of response, time to treatment failure, safety (NCI CTCAE v3.0 adverse events [AEs] and AEs of special interest for BEV), quality of life (FACT-B), and translational research. The primary analysis of PFS was prespecified after 310 investigator-assessed PFS events. The statistical design provided 90% power to detect a PFS hazard ratio (HR) of 0.69 (median PFS 11→16 months) with α=0.05. Results: Between Sep 2006 and Feb 2010, 424 patients were enrolled from 60 centers; 421 received treatment. Baseline characteristics were generally well balanced in the H + DOC and H + DOC + BEV arms: median age 55 and 53 years, respectively; visceral metastases 71% and 77%; prior adjuvant H 12% and 13%; disease-free interval No new safety signals were observed. The following grade ≥3 AEs were more common in the BEV-containing arm than the H + DOC arm: congestive heart failure (5.1% vs 2.9%, respectively); febrile neutropenia (11.6% vs 8.7%); hypertension (11.6% vs 0.5%). Grade 5 AEs occurred in 1.4% of the H + DOC + BEV arm vs 1.9% of the H + DOC arm. Conclusions: The addition of BEV to H + DOC improved PFS without reaching statistical significance according to investigator assessment (unstratified HR 0.82; 95% CI 0.65−1.02). The improvement as assessed by Independent Review Committee was statistically significant. Evaluation of biomarkers is ongoing to try to identify those patients who may benefit from first-line BEV-containing therapy for HER2−positive LR/mBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-8.