Anti-Angiopoietin Therapy With Trebananib for Recurrent Ovarian Cancer (TRINOVA-1) (2014)

Angiogenesis has become an important target for treatment of epithelial ovarian cancer. The growth of new blood vessels is critical for cancer growth, metastases, and progression. Vascular endothelial growth factor (VEGF) plays a key role in epithelial ovarian cancer. Adding anti-VEGF treatment to first-line chemotherapy, to maintenance therapy, or at the time of recurrence significantly prolongs progression-free survival. However, these agents have several adverse effects, including hypertension, thrombosis, emboli, bleeding, impaired wound healing, proteinuria, and bowel perforation. As many as a third of patients with epithelial ovarian cancer discontinue anti-VEGF treatment because of these adverse events. Trebananib has a mechanism of action and toxicity profile different from other antiangiogenesis agents. It inhibits angiogenesis by preventing the binding of angiopoietins 1 and 2 to the Tie2 receptor. In a randomized phase 2 trial, trebananib prolonged progression-free survival in patients with recurrent epithelial ovarian cancer. This agent has mild and reversible adverse events. Edema is a unique adverse effect. The aim of this randomized, double-blind, placebo-controlled phase 3 trial was to determine whether adding trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer would improve progression-free survival. A total of 919 women with recurrent epithelial ovarian cancer from 32 countries were enrolled between November 10, 2010, and November 19, 2012. Eligible patients had been treated previously with 3 or fewer regimens and also had a platinum-free interval of less than 12 months. Patients were enrolled using a computerized interactive voice response system and were randomized to receive weekly intravenous paclitaxel at 80 mg/m2 plus either weekly masked intravenous placebo (n = 458) or trebananib at 15 mg/kg (n = 461). Patients were stratified according to platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe, Australia, or rest of world). All site staff, investigators, and patients were masked to the treatment assignments. The primary study outcome was progression-free survival. Data were analyzed according to intention-to-treat. At a median follow-up of 10.1 months, median progression-free survival was significantly longer in the trebananib group than in the placebo group (7.2 months; 95% confidence interval [CI], 5.8–7.4 vs 5.4 months; 95% CI, 4.3–5.5], respectively); the hazard ratio was 0.66, with a 95% CI of 0.57–0.77, P < 0.0001. No significant difference was found between treatment groups in the incidence of grade 3 or higher adverse events (placebo: 244 [54%] patients vs trebananib: 258 [56%] patients). Grade 3 or higher adverse events included the following: ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). Edema occurred more frequently among patients in the trebananib group (294 [64%]) than in the placebo group (127 [28%]), but it was generally mild. More adverse event–related treatment discontinuations occurred in the trebananib group than in the placebo group (77 [17%] patients vs 27 [6%] patients, respectively). There was less than a 2% difference between groups in incidence of the class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, impaired wound healing, thrombotic events, and bowel perforation); bleeding was more common in the placebo group (75 [17%] vs 46 [10%]). These findings show that trebananib provides a clinically meaningful prolongation in progression-free survival when added to weekly paclitaxel in the treatment of recurrent epithelial ovarian cancer. Although edema was increased, it was generally mild. Typical anti-VEGF–associated adverse events were not prominent. The data suggest that trebananib may be a non-VEGF antiangiogenesis option in this population.