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Anti-Angiogenesis Therapy With Avastin (Bevacizumab): Presented at IBCEF

By Chris Berrie

VIENNA, AUSTRIA -- February 21, 2006 -- Bevacizumab (Avastin(R)) represents the first anti-angiogenic agent to have a proven clinical benefit for patients with breast cancer, according to an overview of present and ongoing trials presented here at the International Breast Cancer Expert Forum: Milestones in Management, Confidence and Care (IBCEF).

Bevacizumab is a humanised monoclonal anti-vascular endothelial growth factor (VEGF) antibody that has anti-angiogenic actions and is well tolerated, with manageable adverse effects, according to David Miles, MD, Consultant Medical Oncologist, Gray Cancer Institute, Mount Vernon Hospital, Middlesex, United Kingdom, who presented the overview on February 11^th.

The recent development of bevacizumab has led to its being testing in a number of recent and ongoing trials, he said.

In a number of phase 1/2 trials, bevacizumab has been used for patients with locally advanced/recurrent malignant breast cancer, in combination with a number of other therapeutic agents, including vinorelbine, docetaxel, Tarceva(R) (erlotinib), Herceptin(R) (trastuzumab) and letrozole. Following these encouraging results from both the efficacy and safety points of view, a number of combinations have been taken into further phase 2/3 trials, Dr. Miles said.

In the AVF2119g phase 3 trial of oral capecitabine (Xeloda(R)) 2500 mg/kg daily for 2 weeks without (n = 230) and with (n = 232) bevacizumab (15 mg/kg IV every 3 weeks) in previously treated metastatic breast cancer, the primary endpoint of median progression-free survival (PFS) was 4.17 and 4.86 months, respectively (hazard ratio [HR], 0.98; P = .857), indicating no additional benefit of bevacizumab.

However, the overall response rates of the independent review facility showed a significant improvement with bevacizumab, from 9.1% to 19.8% (P = .001), respectively, which was accompanied by an increase in grade III hypertension (0.5% to 17.9%, respectively) as the only major difference in the grade III/IV adverse events.

In the E2100 randomised phase 2 trial of paclitaxel 90 mg/m² on days 1, 8, 15 without (n = 350) and with (n = 365) bevacizumab 10 mg/kg on days 1, 15 as first-line therapy for locally recurrent or metastatic breast cancer, the PFS was indeed improved in the presence of bevacizumab (11.4 months, vs. paclitaxel at 6.11 months; HR, 0.51; 95% confidence interval [CI], 0.43-0.62; P < .0001). Similarly, bevacizumab significantly improved response rates for measurable disease improved (37.7% vs. 16.0%; P <. 0001). The significance also carried through to the subgroup analyses for PFS (except for the ER+, PR- and age 65-85 subgroups). The only major increase in grade III toxicity was hypertension (15% vs. 2%).

Dr. Miles outlined ongoing bevacizumab trials. The first of these is the randomised, double-blind, placebo-controlled, multicentre AVADO (BO17708) phase 3 trial with previously untreated patients with MBC (n = 705). The three regimens include docetaxel 100 mg/m² every 3 weeks without and with bevacizumab 7.5 and 15 mg/kg every 3 weeks.

The Eastern Cooperative Oncology Group's E2104 phase 2 randomised trial in patients with breast cancer is evaluating adjuvant bevacizumab 10 mg/kg every 14 days for four cycles in combination with and following both doxorubicin/cyclophosphamide 60/600 mg/m² every 14 days for four cycles and secondary paclitaxel 175 mg/m² every 14 days for four cycles. This includes the primary endpoint of clinically apparent cardiac dysfunction.

Finally, Dr. Miles outlined the National Cancer Institutes' randomised, double-blind, placebo-controlled TORI-B-02 trial of bevacizumab in the neoadjuvant setting in breast cancer (n = 90). This phase 2 study will follow an alternating protocol from initial bevacizumab alone 7.5 and 15 mg/kg, each vs. placebo, through the inclusion of docetaxel, doxorubicin and cyclophosphamide, and back to bevacizumab alone, with the primary endpoint of safety.

While Dr. Miles stressed that bevacizumab is indeed the first anti-angiogenic agent to have shown clinical benefit in breast cancer, he also indicated that bevacizumab provides greater clinical benefit when it is used in patients who have not been heavily pretreated.

He added that the ongoing studies in neoajuvant, adjuvant and metastatic settings with bevacizumab in combination with other agents promises to provide further evidence of a role for bevacizumab in the treatment of patients with breast cancer.

The conference was sponsored by Roche.


[Presentation title: Anti-angiogenesis Therapy With Avastin(R): a New Paradigm to Improve Survival.]

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