The potential of Avastin (bevacizumab), Roche’s reliably controversial oncology drug, as second-line therapy for advanced breast cancer received a boost from data presented at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium in the US last week.

Results from the RIBBON 2 study showed that women given Avastin in combination with standard chemotherapies as second-line treatment for advanced HER2-negative breast cancer had a 28% improvement in progression-free survival (PFS) or the chance of staying alive without the disease getting any worse.

But an interim analysis of overall survival (OS) in the RIBBON 2 trial did not produce any statistically significant difference between patients on Avastin plus chemotherapies and those on chemotherapies plus placebo.

Another trial presented at the CTRC-AACR meeting, involving Avastin in combination with docetaxel (Taxotere, Sanofi-Aventis) versus placebo plus docetaxel for first-line treatment of locally recurrent or metastatic breast cancer, also showed a significant increase in PFS in the Avastin arms but no improvement in overall survival.

Roche said the RIBBON 2 outcomes were important as most women with advanced breast cancer will see their disease progress once the initial chemotherapy stops working. At the moment, it added, the only option for these women is more chemotherapy.

“This is the first Phase III study to show that the combination of an anti-angiogenic medicine with commonly used second-line chemotherapy can extend the time women with advanced breast cancer live without the disease worsening,” commented Dr Adam Brufsky, principal investigator and medical director of the Women’s Cancer Center, University of Pittsburgh Medical Center in the US.

As Brufsky et al noted, a previous Phase III study (AVF2119g), in which patients with, in the main, heavily pretreated metastatic breast cancer were given Avastin as an add-on to capecitabine (Xeloda, Roche), resulted in a significant improvement in the objective response rate (ORR) but did not meet the primary endpoint for PFS.


In the RIBBON-2 study, a total of 684 patients at sites in 19 countries were randomised 2:1 to chemotherapy (investigator’s choice, including paclitaxel, docetaxel, gemcitabine, capecitabine and vinorelbine) plus Avastin or to chemotherapy plus placebo.

This trial did meet its primary endpoint of progression-free survival pooled across the chemotherapy cohorts, with median PFS of 7.2 months in the chemotherapy plus Avastin arm (459 patients) and of 5.1 months in the chemotherapy plus placebo arm. The ORR was 10 percentage points higher in the Avastin than the placebo group (39.5% versus 29.6%).

However, overall survival at the interim analysis stage (57% of events recorded) failed to reach statistical significance, with median OS of 18.0 months on chemotherapy plus Avastin and 16.4 months on chemotherapy plus placebo.

AVADO data

The other presentation, one of several on Avastin at the CTRC-AACR symposium, was of final overall survival data from AVADO, a Phase III study of Avastin plus docetaxel compared with placebo plus docetaxel in the first-line treatment of locally recurrent or metastatic breast cancer.

A total of 736 patients were randomised to docetaxel plus placebo or to docetaxel plus two different doses of Avastin (7.5 mg/kg or 15mg/kg respectively). In the primary analysis (data cut-off point: October 2007; median follow-up of 10.2 months – patients were enrolled between March 2006 and April 2007), there were significant improvements in PFS and ORR for both the Avastin arms compared with docetaxel plus placebo.

Median PFS, for example, was 8.1 months on docetaxel plus placebo, 9.0 months on docetaxel plus Avastin 7.5mg/kg, and 10.0 months on docetaxel plus Avastin 15mg/kg.

But mature OS data (data cut-off point: April 2009; median follow-up of 25 months) did not produce a statistically meaningful survival benefit for either of the Avastin groups. Median overall survival was 31.9 months in the docetaxel plus placebo arm, 30.8 months for docetaxel plus Avastin 7.5mg/kg, and 30.2 months for docetaxel plus Avastin 15mg/kg.

The researchers presenting the overall survival results from AVADO suggested the lack of differentiation might be due to the study design, whereby patients were initially given docetaxel on a three-weekly basis for around nine cycles and Avastin or placebo three weekly until disease progression or unacceptable toxicity.

After progression, patients were offered Avastin with second-line anticancer therapy in a post-study treatment phase. An exploratory analysis in those receiving post-progression chemotherapy compared overall survival in patients who were given second-line Avastin and those who were not.

“Recognising the limitations of the non-randomised comparison in exploratory analyses, results suggest that use of bevacizumab with second-line therapy is a possible reason for lack of OS difference,” the authors stated.

The annual CTRC-AACR symposium is organised by the Cancer Therapy & Research Center (CTRC) at UT Health Science Center, San Antonio and the American Association for Cancer Research (AACR).