Bevacizumab plus fosbretabulin improves PFS* in ovarian cancer


AT IGCS 2014


MELBOURNE – The combination of the antiangiogenesis drug bevacizumab and the vascular-disrupting agent fosbretabulin is superior to bevacizumab alone in the treatment of recurrent ovarian, tubal, and peritoneal cancer, according to an oral presentation made at the biennial meeting of the International Gynecologic Cancer Society.

A randomized, open-label, phase II study in 107 patients found a significant improvement in progression-free survival among patients treated with the combination of bevacizumab and fosbretabulin versus bevacizumab alone (hazard ratio, 0.685; P = .049), with a median improvement of 2.5 months.

Researchers observed a greater improvement in progression-free survival among patients with platinum-resistant disease, with a 3.3-month improvement (HR, 0.57; P = .01), but the difference in platinum-sensitive patients failed to reach statistical significance.

Patients in the combination arm also showed a higher response rate than those in the single-therapy arm.

Presenter Dr. Bradley Monk said the challenge with using antiangiogenesis agents alone was that they only dealt with new blood vessel growth.

“The Achilles’ heel of angiogenesis is, what about the blood vessels that are already there?” said Dr. Monk, director of gynecological oncology at the University of Arizona Cancer Center and Dignity Health, both in Phoenix.

Dr. Monk said antivascular agents such as fosbretabulin collapse the established tumor blood vessels, causing mechanistic obstructions that lead to tumor necrosis, and because of their tolerability, they can be combined with chemotherapy and antiangiogenesis agents.

While this approach has been considered before, not all vascular-disrupting agents were suitable.

“There are different types of vascular-disrupting agents. They’re not all the same, and, in fact, there are vascular-disrupting agents that have not worked,” Dr. Monk said in an interview.

He told the conference that fosbretabulin is a potent and reversible tubulin depolymerizing agent, targeting the tubulin cytoskeleton that is so important in tumor-associated blood vessels, which lack smooth muscle and pericyte coverage and rely on tubulin to maintain their structure.

The combination approach was associated with a significantly higher incidence of adverse events, compared with bevacizumab alone, and 16.7% of patients in the combination arm came off the study because of adverse events, compared with 5.7% of patients in the monotherapy arm.

There were more cases of grade 3 hypertension in the combination arm than in the monotherapy arm, which Dr. Monk said was a known side effect of fosbretabulin.

There was one grade 4 hypertension event in the combination arm, and one grade 4 metabolism-related adverse event in the bevacizumab-alone arm.

Data on overall survival were not mature, but Dr. Monk said that based on these results, the combination of fosbretabulin and bevacizumab warranted further study in ovarian cancer.

The study was sponsored by the National Cancer Institute. One author is an employee of fosbretabulin manufacturer Oxigene. The presenter declared expenses, consultancies, and research funding from several pharmaceutical companies, including Oxigene.

*Correction, 11/10/2014: A previous version of the headline did not clearly state that the improvement was in progression free survival.

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