RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

University of Pittsburgh, 300 Halket St, Suite 4628, Pittsburgh, PA 15213, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2011; 29(32):4286-93. DOI: 10.1200/JCO.2010.34.1255
Source: PubMed


This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) -negative metastatic breast cancer.
Patients were randomly assigned 2:1 to chemotherapy + bevacizumab or to chemotherapy + placebo. Before random assignment, investigators chose capecitabine, a taxane (paclitaxel, nab-paclitaxel, or docetaxel), gemcitabine, or vinorelbine. Dosing for bevacizumab or placebo was 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, depending on chemotherapy regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, PFS by chemotherapy cohort, objective response rate (ORR), duration of objective response, 1-year survival rate, and safety.
RIBBON-2 enrolled 684 patients (225, chemotherapy + placebo; 459, chemotherapy + bevacizumab). The combination of bevacizumab with chemotherapy demonstrated a statistically significant benefit. Median PFS increased from 5.1 to 7.2 months (stratified hazard ratio for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). The 10% improvement in ORR between the placebo- and bevacizumab-containing arms (39.5% v 29.6%; P = .0193), although not statistically significant, was consistent with previous trials. There was no statistically significant difference in overall survival. The most common grade ≥ 3 adverse events (AEs) related to bevacizumab treatment were hypertension (9.0%) and proteinuria (3.1%). There was an increased number of AEs leading to study discontinuation in the chemotherapy + bevacizumab arm compared with the chemotherapy + placebo arm (13.3% v 7.2%).
The combination of bevacizumab with commonly used chemotherapies improved PFS in the second-line treatment of patients with HER2-negative metastatic breast cancer, with a safety profile comparable with that in prior phase III studies.

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    • "Bevacizumab also gained accelerated US-FDA approval for metastatic breast cancer based, in part, on the results of ECOG-2100 (Miller et al, 2007), a randomised phase III trial of paclitaxel with or without bevacizumab. On the basis of less absolute differences in progression-free survival in later trials (AVADO, RIBBON-I, and RIBBON-II (Miles et al, 2010; Brufsky et al, 2011; Robert et al, 2011)), no overall survival benefit, and due to the unique and unpredictable toxicity profile, bevacizumab's US-FDA approval for breast cancer was rescinded (FDA NEWS RELEASE, 2011). Despite this, bevacizumab has remained an approved treatment for breast cancer in the European Union. "
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    ABSTRACT: Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. Methods: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3–5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. Results: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10−8; OR=3.3) and in the cumulative dose model (P=4.7 × 10−8; HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3–5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). Conclusions: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.
    Full-text · Article · Aug 2014 · British Journal of Cancer
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    • "The study of Robert et al. [29] compared standard chemotherapy (capecitabine or taxanes/anthracyclines) with or without bevacizumab for first line treatment of HER-2 negative locally recurrent or metastatic breast cancer. Instead Brufsky et al. [30] tested bevacizumab in the second line setting. In these two studies the allocation between the experimental arm and control arm had a low risk of bias (due to the description of allocation concealment and the random sequence generation); however, the investigators chose which chemotherapy to treat the patient with before randomization, which could have led to a loss of balance in treatment assignment and a relevant shift in the direction and magnitude of the effect. "
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    ABSTRACT: Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective. To assess the role of biological agents in metastatic triple-negative breast cancer we performed a systematic review of phase III randomized controlled trials published from January 2006 to February 2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010–2012. We consulted PubMed and Only studies comparing biological agents and chemotherapy versus chemotherapy alone were considered. Relevant statistical variables were log of the hazard ratio and relative variance for progression-free survival (PFS) and overall survival (OS). Of 353 PubMed publications and 229 studies registered on, ten trials were selected and 5,293 patients were analyzed: 1,546 had mTNBC. Biological agents considered were bevacizumab, sunitinib, sorafenib, lapatinib, iniparib and cetuximab. In addition, a meta analysis of the 4 studies containing bevacizumab was performed and it showed a PFS improvement with a relative risk reduction of 35% (95% CI: 25%-43%). No effect on OS was observed. No PFS and OS benefit was detected with the other agents. No improvement of OS was detected in patients treated with biological agents plus chemotherapy, while a significant PFS improvement was observed only for bevacizumab and cetuximab. The overall impact of these agents on patient survival was not as great as expected, probably because the molecular basis of this illness needs to be better understood so that treatment can be more appropriately tailored.
    Full-text · Article · Jun 2014 · Cancer Treatment Reviews
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    • "The 5-year survival rate for women with breast cancer is 99% for those with localized disease and 84% for regional disease, and only 24% in patients with distant disease (Siegel et al. 2014). Several studies in human epidermal growth factor receptor 2 (HER2)-normal metastatic breast cancer have reported that the addition of bevacizumab to chemotherapy improves response rates and progression-free survival compared with chemotherapy alone (Miller et al. 2007; Robert et al. 2009; Brufsky et al. 2011; Pivot et al. 2011). Preclinical evidence also suggests that the combination of monoclonal antibodies that target HER2 and vascular endothelial growth factor (VEGF) may act synergistically in HER2 overexpressing cancers (Sweeney et al. 2001; Pegram et al. 2004). "
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    ABSTRACT: PurposeAdding antiangiogenic therapy to standard chemotherapy has improved response rates and progression-free survival in metastatic breast cancer (BC) patients. This phase II study evaluated cardiac safety of bevacizumab with/without trastuzumab with two docetaxel-based regimens in early BC.Methods127 women with non-metastatic node-positive or high-risk node-negative BC were enrolled. Women with human epidermal growth factor receptor 2 (HER2)-negative BC (n = 93) received docetaxel/doxorubicin/cyclophosphamide (TAC) + bevacizumab, while women with HER2-positive disease (n = 34) received docetaxel/carboplatin/trastuzumab (TCH) + bevacizumab, every 3 weeks for six cycles. Maintenance therapy with bevacizumab alone or bevacizumab plus trastuzumab, respectively, was given every 3 weeks for 52 weeks. The primary objective was to evaluate cardiac safety, as measured by the incidence of ≥ grade 3 clinical congestive heart failure (CHF); the secondary objective was assessment of safety and toxicity.ResultsAt least one cardiac adverse event (AE; CHF, cardiomyopathy, or left ventricular dysfunction) was reported in 26.1% of TAC (n = 92) and 17.6% of TCH subjects (n = 34); there were no cardiac deaths. ≥ Grade 3 clinical CHF was observed in 4.3% in the TAC plus bevacizumab stratum and 0% in the TCH plus bevacizumab stratum. A ≥ grade 3 treatment-emergent AE (any kind) related to study treatment was observed in 59.8% in the TAC with bevacizumab and 52.9% in the TCH plus bevacizumab stratum.ConclusionAdding bevacizumab to a docetaxel-based regimen with trastuzumab did not appear to increase cardiotoxicity.Trial Identifier: NCT00446030, registered March 8, 2007.
    Full-text · Article · May 2014 · SpringerPlus
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