RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC)
Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2009
Presenter: N. J. Robert Presenter's Affiliation: US Oncology Group Type of Session: Scientific
Bevacizumab (B) is a humanized monoclonal antibody which inhibits VEGF, a known central mediator of angiogenesis.
Two previous large phase III trials, E2100 and AVARO, have demonstrated that B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone.
However, there is current a lack of evidence supporting the use of B in combination with other non-taxane agents used at 1st-line treatment for MBC.
The RIBBON-1 study is a randomized Phase III trial that was designed to investigate the clinical benefit of combining B with various standard 1st-line chemotherapy regimens for MBC.
Materials and Methods
Patients with previously untreated histologically confirmed locally recurrent or metastatic HER2 neu negative breast cancer.
Age > 18
ECOG performance status 0 or 1
> 12 months since prior neoadjuvant or adjuvant chemotherapy
No CNS metastases
Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy.
Prior to randomization, investigators were allowed to choose which chemotherapy they preferred to use. They could choose from capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk).
B or pl was administered at 15 mg/kg q3wk.
If patient’s had disease progression after initial treatment, physicians had the option of starting them on 2nd line chemotherapy + B.
The primary endpoint was PFS as assessed by the investigator.
Secondary endpoints included PFS assessed by and independent review committee (IRC), objective response rate (ORR), overall survival (OS), 1-year survival rate, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy.
The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test
Cap cohort: 80% power to detect HR=0.75 with planned sample size of 600.
T + Ant cohort: 90% power to detect HR=0.70 with planned sample size of 600.
1237 patients (Cap, 615; T, 307; Ant, 315) from > 200 sites in 22 countries were enrolled on this study between December 2005 and August 2007. Data obtained after July 31, 2008 was not used.
206 patients were in the Cap+pl group, 409 patients were in Cap+B group, 207 patients were in the T+Ant+pl group, and 415 patients were in the T+Ant+B group
Median follow-up was 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort.
Patient baseline characteristics were well-balanced between the two arms.
One-third of patients had died at time of analysis.
Efficacy results for Cap+pl vs. Cap+B:
p-value and HR
Efficacy results for T+Ant+pl vs. T+Ant+B:
p-value and HR
Proteinuria and HTN rates were higher in all 3 groups, similar to that seen in bevacizumab previous studies.
The addition of B to chemotherapy regimens used in 1st line treatment of MBC led to statistically significant improvements in PFS, both assessed by investigator and IRC, and in ORR.
There was no difference seen in OS with the addition of B.
The safety profile of this study was comparable to the 2 prior phase III studies done in this area.
RIBBON-1 provides a third randomized phase III trial demonstrating the efficacy and safety of adding B with 1st line chemotherapy for MBC.
It also was the 1st phase III trial to test non-taxane chemotherapy with B.
The results presented for the RIBBON-1 trial confirm the results present previous phase III trials such as E2100 and AVARO, which also examined the benefit of B with chemotherapy for metastatic breast cancer patient with similar patient characteristics
Efficacy results were similar between the 3 trials. There was a relative increased in response rate of 20-50% with B treatment seen in all these studies.
While the other 2 previous trials provided data for only taxane chemotherapy with B, this trial demonstrated a benefit with adding B with other commonly used chemotherapeutic agents as well. In addition, this trial was placebo-controlled, unlike the E2100 study.
RIBBON-1 met its primary endpoint of PFS (assessed by both the investigator and IRC) compared to chemotherapy alone. B also increased ORR and was well-tolerated.
Strengths of the study:
Large, contemporaneous population. The patients in this study represented the average patients with metastatic breast cancer seen in clinic.
Multiple chemotherapy regimens were allowed which make this study more generalizable to be used in clinics worldwide where various agents are used.
An independent review committee was used to assess PFS which helps to eliminate investigator bias.
Limitations of the study:
This trial was really composed of 2 separate studies conducted in parallel. This makes it difficult to compare between the 2 chemotherapy regimens that were analyzed separately.
Neither chemotherapy group was powered to assess OS. Larger numbers of patients on this trial would be needed to observe a survival benefit.
Additionally, about 50-60% of patients crossed-over to other agents + B in the placebo groups, which is a confounding factor when analyzing survival data.
From the results of this well-designed Phase III trial, we can conclude from that B is likely an important component for intial chemotherapy for Her2neu negative metastatic breast cancer patients.
Other interesting questions which should be addressed in future studies include:
Will combination of B with trastuzamab or Her2neu targeted therapies for patients with metastatic Her2neu+ cancers lead to increased efficacy?
Can we combine with B with hormonal treatments such as Tamoxifen or AIs and see clinical benefit?
What is the optimal duration of treatment with B?
Does the choice of chemotherapy matter? Are there differences in chemotherapy effects with B?
Further study of B with other agents in both breast cancer patients and patients with other cancer type should continue as it is a promising agents that shows potential to be used in various clinical settings.
Jun 6, 2012 - Continuing use of bevacizumab (Avastin) in combination with second-line chemotherapy improves overall survival and progression-free survival in patients with metastatic colorectal cancer who have progressed after discontinuation of first-line bevacizumab and chemotherapy, according to the results of a phase III study presented at the annual meeting of the American Society of Clinical Oncology, held from June 1 to 5 in Chicago.