Antiangiogenesis Pursued in High-Risk Ovarian Cancer

Angiogenesis is an active area of clinical research in ovarian cancer, but proving that this approach extends overall survival (OS) has been somewhat challenging thus far. Michael Bookman, MD, reviewed studies of antiangiogenesis in high-grade serous ovarian cancer at the 2013 Chemotherapy Foundation Symposium, held in New York City. Bookman is the director of medical oncology at the University of Arizona Cancer Center in Tucson.

“High-grade serous ovarian cancer is the most common subtype of epithelial ovarian cancer and it remains highly lethal. New approaches are needed beyond angiogenesis,” he told listeners.

“The key questions to consider in antiangiogenic trials are the best targets, the preferred strategy, and the optimal setting for these studies,” Bookman said. “We need predictive biomarkers and we need to think about how we measure success in clinical trials.”

Trials of Primary Therapy
Studies of frontline therapy have shown that primary therapy with weekly paclitaxel appears to be more effective than other schedules. The value of incorporating antiangiogenesis into up-front regimens is based on exploratory analysis of phase 3 trials, he said.

To date, the addition of an angiogenesis inhibitor, typically bevacizumab, to chemotherapy improves progression-free survival (PFS) but does not extend OS.
Two trials of up-front treatment for high-grade serous ovarian cancer, ICON7 and GOG-0218, showed a modest difference in PFS and no difference in OS with the addition of the anti–vascular endothelial growth factor (VEGF) therapy bevacizumab compared with platinum-based chemotherapy. However, exploratory analysis suggests that patients with moderate- to high-risk bulky disease have better outcomes with bevacizumab.

A contrary finding in the AGO-OVAR12 trial that compared chemotherapy plus or minus nintedanib showed a slight PFS benefit, but in an exploratory analysis, the low-risk group did better with nintedanib. In addition, nintedanib inhibits VEGF receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, and targets tumor cells directly; thus it may have a different effect than bevacizumab, Bookman said.

The AGO-OVAR16 trial showed that maintenance therapy with pazopanib (a tyrosine kinase inhibitor) improved PFS but had no effect on survival.
Weekly paclitaxel was identified as the preferred schedule for this drug, improving both PFS and OS. The next trial looked at weekly paclitaxel plus or minus bevacizumab.

GOG-0262/ACRIN 6695 showed no difference in PFS with the addition of bevacizumab to chemotherapy. In an exploratory analysis, median PFS was 10.6 months in patients treated with weekly paclitaxel minus bevacizumab and 14.2 months with the addition of bevacizumab.

Thus, weekly paclitaxel and bevaciz- umab had the best results.

A biomarker substudy of GOG-0262 suggested that weekly paclitaxel by itself has antiangiogenic effects on tumor blood flow and tumor volume, Bookman noted.

Trials in Advanced Recurrent Disease
The OCEANS trial in platinum-sensitive disease showed that the addition of bevacizumab to chemotherapy improved PFS. The AURELIA study in platinum-resistant disease found that bevacizumab improved PFS. Both trials found no difference in OS favoring the addition of bevacizumab. “These studies suggest that bevacizumab is effective in improving PFS in both platinum-sensitive and platinum-resistant disease,” Bookman said.

In a subset analysis of AURELIA, in which chemotherapy was selected by physician’s choice, the most striking benefits were observed when bevaciz- umab was added to weekly paclitaxel. No additional benefit was seen when bevacizumab was used with pegylated doxorubicin or topotecan, he noted.

The ICON6 trial in recurrent disease found that when added to chemotherapy, cediranib—a potent inhibitor of VEGF tyrosine kinase—improved OS: median OS was 20.3 months without cediranib versus 26 months when this agent was added.

The TRINOVA-1 trial evaluated the addition of trebananib to chemotherapy. Trebananib is an investigational antiangiogenesis recombinant peptide that inhibits the binding of angiopoietin 1 and 2 to the Tie2 receptor—a different target than that of bevacizumab. In that study, PFS was extended with trebananib. Survival results are not yet available.

Trebananib has a different toxicity profile that includes edema, pleural effusion, ascites, and weight increase. Bookman suggested that these treatment-emergent adverse events may predict clinical response to this novel agent.

The GOG-3001 trial is evaluating carboplatin/paclitaxel plus or minus treban- anib, and the trial is beginning accrual.

Remaining issues include the best target for antiangiogenesis—VEGF receptors, angiopoietin 1 and 2?

“The cellular target of angiogenesis is not obvious,” Bookman continued. “It is not clear which is better—to target the vascular endothelium or directly target the tumor.”

Reference
Bookman M. Perspective on antiangiogenic trials in ovarian cancer. Presented at: 2013 Chemotherapy Foundation Symposium; November 7, 2013; New York, NY.