Combining Antiangiogenic and Vascular-Disrupting Agents Improves Progression-Free Survival in Persistent Ovarian Cancer


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Bradley J. Monk, MD

Bevacizumab as a single agent is active and well tolerated, and patients can stay on treatment for a long time. When you add fosbretabulin, they can stay on treatment even longer.

—Bradley J. Monk, MD

“Bevacizumab [Avastin] prevents new blood vessels from growing, but what about the blood vessels that are already in the tumor?” Presenting that challenge to participants at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in Chicago, Bradley J. Monk, MD, of the University of Arizona Cancer Center in Phoenix, then suggested combining bevacizumab with an agent from “the complementary class of antivascular agents that target existing blood vessels” to “capitalize” on results produced by bevacizumab in patients with persistent or recurrent ovarian cancer. This complementary class of agents, called vascular-disrupting agents, Dr. Monk explained, can cause vascular collapse, reduce tumor blood flow, and are unlikely to lead to resistance, based on their mechanism of action.

A phase I study1 showed that combining the antiangiogenic agent bevacizumab with the vascular-disrupting agent fosbretabulin produced a “39% persistent reduction in vascularization,” Dr. Monk said. “This led to a randomized phase II trial, trying to assess whether the addition of fosbretabulin to bevacizumab could do better than what we had done with bevacizumab as a single agent,” Dr. Monk stated.

‘Intriguing, Positive Study’

The phase II study compared bevacizumab and fosbretabulin with bevacizumab alone among patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal carcinoma. Fosbretabulin is a water-soluble prodrug of cis-combretastatin A4 (cis-CA4), a natural product isolated from the African bush willow (Combretum caffrum). The study was conducted by NRG Oncology and the Gynecologic Oncology Group.

“This was a very intriguing, positive study,” Dr. Monk reported. “Patients were randomized in an open-label fashion to bevacizumab vs bevacizumab/fosbretabulin given every 3 weeks,” Dr. Monk explained. The intent-to-treat population of 107 patients included 54 patients who received the combination of bevacizumab and fosbretabulin and 53 patients who received bevacizumab alone. A total of 103 patients were evaluable, 52 treated with the combination and 51 treated with bevacizumab alone.

“Patients “were well balanced in regard to age, ethnicity, performance status, cell type, and number of prior regimens,” Dr. Monk said. Most patients in both treatment groups were between 50 and 80 years old, and 85% in both groups had serous cell tumors. Most patients, 77.8% in the combination group and 73.6% in the bevacizumab-alone group, had measurable disease.

Patients were allowed to have one to three prior chemotherapy regimens with no more than one nonplatinum, nontaxane regimen. Prior front-line bevacizumab was also allowed. “Interestingly, there were only 5 patients in each arm, a total of 10, who had had prior bevacizumab,” Dr. Monk noted.

Statistically Significant Improvement

“When fosbretabulin was added to bevacizumab, there was a statistically significant improvement in progression-free survival,” Dr. Monk reported. The median progression-free survival was 7.3 months in the combination arm, compared with 4.8 months in the bevacizumab-alone arm, with a hazard ratio of 0.685. Among platinum-resistant patients, the median progression-free survival was 6.7 months with combination treatment vs 3.4 months with bevacizumab alone. “We wanted to look at the resistant patients,” Dr. Monk noted, “because they are the highest unmet medical need.”

The difference in median progression-free survival among platinum-sensitive patients with a platinum-free interval of more than 6 months was 7.6 months for the combination treatment vs 6.1 months for bevacizumab alone, but “the hazard ratio was still 0.67.”

Noting that the study was “a small phase II trial,” and the results were “hypotheses-generating,” Dr. Monk said, “I think this proves that vascular disruption is important and that we can add vascular-disrupting agents and antiangiogenic medications together.” Based on these results, he added, “the combination regimen warrants further evaluation in ovarian cancer.”

Dr. Monk pointed out that the median progression-free survival for platinum-resistant patients in this study was “exactly the same” as in the AURELIA study of single-agent chemotherapy with or without bevacizumab—6.7 months with the combination therapy and 3.4 months with single-agent chemotherapy alone.2 The AURELIA study formed the basis of the U.S. Food and Drug Administration’s (FDA) approval in November 2014 of bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topetecan for the treatment of patients with platinum-resistant recurrent ovarian, fallopian tube, or primary peritoneal cancer.3

Response Rates Increased

In the phase II trial reported by Dr. Monk, the objective response rates among the intent-to-treat population were 27.8% for bevacizumab plus fosbretabulin vs 20.8% for bevacizumab alone. For patients with measurable disease, objective response rates rose to 35.7% in the combination group and 28.2% in the bevacizumab-alone group. The odds ratio for responding to the combination vs single-agent treatment was 1.41.

“There was long-term control and an increase in response rate,” Dr. Monk stated. “Overall survival data are immature, with only 33 patients having died.”

‘Relatively High’ Hypertension

Treatment was tolerable for patients in both groups. “There were patients in both arms who had more than 9 cycles,” Dr. Monk said. Previous experience, he said, has shown that “bevacizumab as a single agent is active and well tolerated, and patients can stay on treatment for a long time. I am here to tell you that when you add fosbretabulin, they can stay on treatment even longer.”

Hypertension “is relatively high,” Dr. Monk noted. Grade 3 hypertension occurred in 37.2% of patients in the combination arm compared with 19.6% in the bevacizumab-alone arm. There were no grade 5 adverse events in either arm, but there was one grade 4 event on each treatment arm, related to hypertension in the combination arm and metabolism/nutrition in the bevacizumab-alone arm. There was also one bowel perforation in the bevacizumab-alone arm. “All adverse events were manageable,” Dr. Monk reported. ■

Disclosure: Dr. Monk’s institution has received funding from the Gynecologic Oncology Group, NRG Oncology, and Genentech. Dr. Monk has received honoraria from and is a consultant and speaker for Genentech. 

References

1. Nathan P, Zweifel M, Padhani AR, et al: Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer. Clin Cancer Res 18:3428-3439, 2012.

2. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32:1302-1308, 2014.

3. National Cancer Institute: FDA approval for bevacizumab. Available at http://
www.cancer.gov/cancertopics/treatment/drugs/fda-bevacizumab. Accessed April 21, 2015.


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