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)

Abstract

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 <6/<12 months after the last dose, respectively. Patients with CNS metastases were excluded. Patients were stratified according to adjuvant H, prior (neo)adjuvant taxane (further stratified by time to relapse since last dose of [neo] adjuvant chemotherapy/no chemotherapy), hormone receptor status, and measurable disease, and were randomized to receive either H (8 mg/kg → 6 mg/kg q3w) + DOC (100 mg/m2 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 <12 months 43% in both arms; measurable disease 85% in both arms. Median follow-up was 26 months in both arms. Efficacy results are summarized in the table. 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.

Bevacizumab-Induced Normalization of Blood Vessels in Tumors Hampers Antibody Uptake

“…More importantly findings in the clinic show that bevacizumab treatment does not contribute favorably to the effect of trastuzumab and support the idea that vessel normalization by bevacizumab has the same effects in patients. In patients with HER2-positive metastatic breast cancer, the combination of bevacizumab and trastuzumab showed only a minimal-to-no improvement in progression-free survival 20,21). Combination studies of bevacizumab plus another antibody have shown a detrimental or only modestly beneficial effect.…”

“…Although there is no clear evidence yet for this phenomenon at the tumor level, 2 large clinical colon cancer trials have shown that combining bevacizumab with cetuximab or panitumumab was less effective than either antibody alone (18,19). Also, 2 randomized studies in patients with human EGF receptor 2 (HER2)-positive metastatic breast cancer showed disappointing impact of adding bevacizumab to trastuzumab (20,21). It is therefore of interest to clarify whether bevacizumab impairs tumor uptake of other antibodies.…”

The Intriguing Role of Bevacizumab in Advanced Breast Cancer – The Search Continues

“…Adding to the controversy, further results of the AVEREL study were recently reported and showed that adding bevacizumab to standard therapy prolongs PFS by about three months in women with HER2-positive locally recurrent or metastatic breast cancer. 25 This benefit of added bevacizumab was similar across most subgroups, except among patients aged 65 years or older and those with measurable disease, in which the benefit was greater. The ORR was significantly higher in the bevacizumab group.…”

Bevacizumab in Neoadjuvant Treatment for Breast Cancer

“…2 We are hopeful that these controversies will indeed kindle a fire in the research community so that clinical trials are conducted in a smarter and more efficient manner. We also sincerely hope that effective predictive markers, perhaps as suggested by data from A Randomized Phase III Trial to Evaluate Bevacizumab in Combination with Trastuzumab Plus Docetaxel as First-Line Therapy for HERZPositive Locally Recurrent/Metastatic Breast Cancer (AVEREL, NCT00391092), 3 will advance the use of antiangiogenic agents.…”

“…However, it is questionable whether these cutoff values were appropriate, given the known iodine deficiency among young women in the United Kingdom 2 and indeed in a subgroup of women in the trial. 3 If reference ranges derived from iodine-sufficient populations 4,5 had been used, the cutoffs would have been lower for thyrotropin and higher for free thyroxine, thereby increasing the number of women who would have been treated (along with their respective controls). (Incidentally, the units of free thyroxine have been inaccurately converted on page 494 of the article.)…”