Fosbretabulin and Avastin Combo Delays Progression, But Doubles Hypertension in Ovarian Cancer

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 Avastin (bevacizumab) compared with Avastin alone, according to data from the phase 2 GOG186i study; however, hypertension rates were double in patients receiving the combination regimen.

In the phase 2 trial, the risk of disease progression was reduced by 31.5 percent with fosbretabulin/Avastincompared with single-agent Avastin (7.3 versus 4.8 months). At the time of the analysis, data on overall survival (OS) were not yet mature.

Avastin 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 moderate to severe hypertension was 35 percent with the combination versus 16% with single-agent Avastin.

Bradley J. Monk, presented findings during 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,” said Monk, professor of gynecologic oncology at the University of Arizona Cancer Center. “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 to 3 prior regimens of chemotherapy were randomized to Avastin or Avastin plus fosbretabulin. Patients received treatment every three weeks until disease progression or unacceptable levels of toxicity occurred.

The randomization was stratified by disease status (measurable versus nonmeasurable), prior Avastin and platinum-free interval. The study’s primary objective was to assess whether the addition of fosbretabulin to Avastin 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 Avastin alone was 28.2 percent among 39 patients with measurable disease. The ORR with the combination regimen was 35.7 percent in 42 patients. The odds ratio for responding to the combination arm relative to the Avastin arm was 1.41.

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 Avastin arm was 19.6 percent compared with 32.7 percent 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 Avastin group and a hypertension-related AE in the bevacizumab and fosbretabulin group. Additionally, one bowel perforation occurred in the Avastin 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 3 study to explore the combination of fosbretabulin and Avastin has not yet been initiated, a phase 2 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.