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Antiangiogenesis Strategy Not Ready for Prime Time: Presented at SABCS

By Charlene Laino

SAN ANTONIO, TX -- December 13, 2002 -- Combination therapy with vinorelbine and the angiogenesis inhibitor bevacizumab does not appear to be dramatically superior to vinorelbine alone in the treatment of women with advanced refractory breast cancer, a phase II trial suggests.

Nevertheless, the combination therapy is relatively nontoxic, suggesting that bevacizumab-based therapies might prove useful once correlative studies define more accurately those patients who are likely to benefit from antiangiogenesis agents, said Harold Burstein, MD, PhD, Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts, United States.

Dr. Burstein presented the results of the new study here on December 12^th during a poster session at the 25^th Annual San Antonio Breast Cancer Symposium.

Bevacizumab is a humanised monoclonal antibody that neutralises vascular endothelial growth factor, a mediator of angiogenesis.

The study was undertaken after laboratory data suggested that vinca alkaloid agents plus angiogenesis inhibitors are more effective than vinca agents alone. Also, the side-effect profile of vinorelbine lends itself to combination with bevacizumab, which was associated with thrombosis, bleeding and hypertension in early clinical trials, Dr. Burstein said.

The trial enrolled 56 women with refractory stage IV breast cancer. The women were administered 10 mg/kg of bevacizumab every 2 weeks and 25 mg/m² of vinorelbine every week until disease progression or undue toxicity.

A two-stage design was used. In the first stage, interim efficacy and safety analyses were performed after accrual of 19 patients. Because of initial activity in more than six patients, the second-stage accrual goal was expanded to 56 patients to test a more rigorous null hypothesis of a 30 percent response rate. With this design, there is an eight percent chance that the combination will prove worthy of further study if the response rate is 30 percent and an 80 percent chance if the response rate is 45 percent.

After a median time on therapy of 5.4 months, 16 of 55 evaluable patients achieved a partial response, and one patient achieved a complete response, yielding a 31 percent response rate. The median time to progression was 5.5 months.

Toxicity analyses disclosed minor cases of hypertension, proteinuria and epistaxis as well as one instance of a pericardial effusion and one grade 3 thrombotic event.

"Overall, acute toxicity is very modest," Dr. Burstein said.

"The time to progression is a little intriguing…but the response rate is [just] OK, about what you'd expect in this heavily pretreated population with vinorelbine alone.

"In light of this and other data presented at the meeting, it is clear we need a correlative marker to tell us which women will really benefit from an antiangiogenesis strategy," said Dr. Burstein, adding that both his team and others are currently looking for such markers.

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