Dr. Monk Discusses Vascular Disrupting Agents in Ovarian Cancer

Bradley Monk, MD

Bradley Monk, MD

Fosbretabulin, a vascular disrupting agent in clinical trials for the treatment for solid tumors, has demonstrated some efficacy in thyroid cancer and is currently being evaluated in combination with the angiogenesis inhibitor bevacizumab for the treatment of ovarian cancer.

To gain insight into this novel approach and its potential benefit,Targeted Oncologyinterviewed Bradley J. Monk, MD, FACOG, FACS, who presented phase II results at the 2015 Society of Gynecologic Oncology’s Annual Meeting on Women's Cancer.

What is fosbretabulin?

Why combine this agent with bevacizumab?

What did this trial find?

Monk is the director of the division of gynecologic oncology and vice chair of the department of obstetrics and gynecology at the University of Arizona Cancer Center-Phoenix.Fosbretabulin is part of a very exciting new class of compounds called vascular disrupting agents. Anti-angiogenesis therapy prevents new blood vessels from growing, but what about those blood vessels that are already in existence? Fosbretabulin is an antitubulin agent that attacks the tubule mechanism, depolymerizing in the new blood vessel endothelial cells. Those vessels are particularly susceptible to tubulin depolymerization because they lack parasites. [With fosbretabulin] we can actually cause vascular collapse of existing blood vessels leading to apoptosis and necrosis. Importantly, drug resistance here is very uncommon.If you kill the blood vessels, they will grow right back. By adding a vascular disrupting agent, you destroy the blood vessels. With an anti-angiogenesis compound, [the blood vessels] cannot grow back, and you have added clinical benefit.We randomized 107 patients with recurrent ovarian cancer to either bevacizumab as a single agent or bevacizumab with the vascular disrupting agent fosbretabulin, every 3 weeks until disease progression or toxicity. We saw an improvement in progression free survival (PFS) and response rate (RR). PFS improved from 4.8 to 7.3 months and RR improved from 28% to 36%.

The most important results were in the platinum-resistant setting. In November, the FDA approved bevacizumab in the setting of platinum-resistant recurrent ovarian cancer. Bevacizumab has demonstrated an improvement in PFS from 3.4 to 6.8 months when added to chemotherapy. In this study, we saw essentially the same result, but there was no chemotherapy.

What are the next steps for fosbretabulin?

Moving forward, our focus is to avoid cytotoxic chemotherapy because it is more toxic. These phase II results were very intriguing for those patients with the highest unmet medical need, platinum-resistant disease.The next step is to do a phase III clinical trial to show that it is better than chemotherapy. That trial is being planned.

Could fosbretabulin expand into other tumor types other than recurrent ovarian cancer?

Anecdotally, what adverse events (AEs) have you seen with fosbretabulin? How should oncology professionals manage those AEs?

What can community oncologists take away from these phase II data?

This [clinical trial] could be practice changing if we can show an improvement in overall survival in the platinum-sensitive space with a regimen containing bevacizumab.It certainly could. As it was with the progression of bevacizumab, the first approval could be in platinum-resistant disease and then could expand into the platinum space. Platinum-resistant disease is the highest unmet medical need.Fosbretabulin, because it causes vascular collapse in the tumor, causes an increase in peripheral resistance and increases hypertension. When adding fosbretabulin to bevacizumab, oncology professionals need to manage these AEs carefully with antihypertensive agents. We [the researchers] didn’t see any gastrointestinal perforations. We didn’t see any strokes or vascular events.Community oncologists should understand that an antivascular agent, which includes both an anti-angiogenesis agent and a vascular disrupting agent, is a valid concept in ovarian cancer. Bevacizumab is active as a single agent.

There is this new class of agents, vascular disrupting agents, which can be safely combined to improve efficacy. This was a hypothesis-generating phase II trial, but it reinforces the importance of antivascular therapy.

I would suggest that all patients, with a focus on toxicity, should receive bevacizumab. It is something to argue about whether to use it as frontline, in platinum-resistant disease, or in the platinum-sensitive space. That can be debated, but I would hate it if patients did not reap the benefits of bevacizumab. It is active, and it is well tolerated.