Fosbretabulin/Bevacizumab Combo Delays Progression, But Doubles Hypertension in Ovarian Cancer

Bradley Monk, MD

Pretreated patients with recurrent ovarian cancer had a 2.5-month progression-free survival (PFS) benefit when receiving the vascular disrupting agent (VDA) fosbretabulin plus bevacizumab compared with bevacizumab (Avastin) alone, according to data from the phase II GOG186i study; however, hypertension rates were double in patients receiving the combination regimen.

In the phase II trial, the risk of disease progression was reduced by 31.5% with fosbretabulin/bevacizumab compared with single-agent bevacizumab (7.3 vs 4.8 months; HR = 0.685; 90% CI, 0.47-1.00;). At the time of the analysis, data on overall survival (OS) were not yet mature (HR = 1.03; 90% CI, 0.56-1.89).

Bevacizumab is known to be active as a single agent against recurrent ovarian cancer, while fosbretabulin selectively targets pre-existing tumor vasculature with a resulting vascular shutdown that leads to cell death and necrosis. Given this mechanism of action, the rates of cardiac events were expectedly higher with the combination. The rate of grade >2 hypertension was 35% with the combination versus 16% with single-agent bevacizumab.

Bradley J. Monk, MD, presented findings during the Seminal Abstract Session at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

“Based on the progression-free survival and tolerability of these two anti-vascular therapies, further evaluation is warranted for this chemotherapy-free regimen, with the understanding that fosbretabulin may increase the frequency of hypertension,” Monk, professor of gynecologic oncology at the University of Arizona Cancer Center, said at the conference. “Overall survival data are currently too early in the timeline to warrant any conclusions, because this was a hypothesis-generating trial. But, in general, we now know that vascular disruption is highly significant.”

In the trial, 107 patients with persistent or recurrent epithelial ovarian, fallopian tube or peritoneal carcinoma, measurable or detectable disease, and 1-3 prior regimens of chemotherapy were randomized to bevacizumab (n = 54; 15 mg/kg IV every 3 weeks) or bevacizumab (15 mg/kg IV every 3 weeks) plus fosbretabulin (n = 53; 60 mg/m2). Patients received treatment every three weeks until disease progression or unacceptable levels of toxicity occurred.

The randomization was stratified by disease status (measurable vs nonmeasurable), prior bevacizumab and platinum-free interval. The study’s primary objective was to assess whether the addition of fosbretabulin to bevacizumab prolongs the duration of PFS. Two secondary objectives were to compare response rates and OS and to evaluate AEs in each study arm.

The objective response rate (ORR) with bevacizumab alone was 28.2% (90% CI, 16.7%-42.3%) among 39 patients with measurable disease. The ORR with the combination regimen was 35.7% in 42 patients (90% CI, 23.5%-49.5%). The odds ratio for responding to the combination arm relative to the bevacizumab arm was 1.41 (90% CI 0.58-3.47).

Both regimens were well tolerated enough for patients to complete a relatively high number of cycles. The median number of cycles with bevacizumab was 7 versus 6 with the combination. Grade 3 hypertension in the bevacizumab arm was 19.6% compared with 32.7% in the combination arm. There was one grade 3 thromboembolic AE.

No grade 5 treatment-related AEs occurred in either study arm. One grade 4 AE occurred in each treatment arm: a metabolism/nutrition-related AE in the bevacizumab group and a hypertension-related AE in the bevacizumab and fosbretabulin group. Additionally, one bowel perforation occurred in the bevacizumab arm, but all adverse events were manageable.

Fosbretabulin is a potent and reversible tubulin depolymerizing agent. It selectively affects immature endothelial cells typically seen in solid tumors, which lack smooth muscle and pericytes and rely more on tubulin to maintain the vessel wall’s flat shape. Tubulin inhibition causes rounding in the affected epithelial cells, obstructing the blood vessel lumen. A blockage at any point in a vessel segment will shut off blood flow upstream and downstream, which leads to rapid death of cells.

“It’s possible that anti-angiogenesis agents like bevacizumab might prevent revascularization during and after VDA treatment,” Monk, professor of gynecologic oncology at the University of Arizona Cancer Center, said at the conference.

Although a phase III study to explore the combination of fosbretabulin and bevacizumab has not yet been initiated, a phase II study is exploring fosbretabulin in patients with gastrointestinal neuroendocrine tumors. Patients in this study are required to have elevations in specific biomarkers, such as serotonin, 5-hydroxyindoleacetic acid, chromogranin A, neurokinin A, and neuron-specific enolase.

Monk, BJ. Randomized phase 2 evaluation of bevacizumab versus bevacizumab/fosbretabulin in recurrent ovarian, tubal or peritoneal carcinoma: a gynecologic oncology group study. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Seminal Abstract 4.

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