Adding Antiangiopoietin Agent Trebananib to Paclitaxel Improves Progression-Free Survival in Recurrent Epithelial Ovarian Cancer
Trebananib inhibits angiogenesis by blocking the binding of angiopoietins 1 and 2 to the Tie2 receptor expressed on endothelial cells, a mechanism that differs from VEGF inhibitors and that involves a different signaling pathway. In the phase III TRINOVA-1 trial reported in The Lancet Oncology, Monk et al found that adding trebananib to paclitaxel significantly prolonged progression-free survival in patients with recurrent epithelial ovarian cancer. The toxicity profile of trebananib was different from that associated with VEGF inhibitors.
Study Details
In this double-blind trial, 919 patients from 32 countries were randomly assigned between November 2010 and November 2012 to receive weekly paclitaxel at 80 mg/m2 plus weekly intravenous placebo (n = 458) or trebananib at 15 mg/kg (n = 461). Eligible patients received one platinum-based regimen for primary disease and two or fewer additional cytotoxic regimens for recurrent or persistent disease, had a platinum-free interval of ≤ 12 months, and could not have received maintenance or consolidation with single-agent paclitaxel.
Previous antiangiogenic therapy was permitted. Patients were stratified according to platinum-free interval (≤ 6 months vs > 6-12 months), measurable disease, and region (North America, western Europe and Australia, or rest of world). The primary endpoint was progression-free survival in the intention to treat population.
The trebananib and placebo groups were generally balanced for age (median, 60 and 59 years), race (84% and 79% white, 13% and 18% Asian), Gynecologic Oncology Group performance status (0 in 56% and 55%, 1 in 43% and 45%), primary tumor (ovarian in 92% and 91%, primary peritoneal carcinoma in 5% in both, fallopian tube in 3% in both), histology (serous in 84% and 85%), histologic grade (eg, poorly differentiated in 59% and 56%, moderately differentiated in 15% and 18%), previous lines of treatment (3 in 20% and 25%, 2 in 38% in both, 1 in 41% and 38%), platinum-free interval (≤ 6 months in 51% and 53%, > 6–12 months in 48% and 46%), previous antiangiogenic treatment (8% in both), measurable disease (94% and 95%), and region (North America for 20% in both, western Europe and Australia for 42% and 41%, and rest of world for 38% and 39%).
Prolonged Progression-Free Survival
After median follow-up of 10.1 months, median progression-free survival was 7.2 months in the trebananib group vs 5.4 months in the placebo group (hazard ratio [HR] = 0.66, P < .0001). The trebananib treatment effect was consistent across most prespecified subgroups, with hazard ratios significantly in favor of trebananib for subgroups with no previous antiangiogenic therapy, white and Asian ethnicity, one and two previous lines of therapy, platinum-free interval of ≤ 6 and > 6 to 12 months, no bulky disease, and age < 70 years. Trebananib was associated with nonsignificantly prolonged progression-free survival in patients with prior antiangiogenic therapy (HR = 0.69, 95% confidence interval = 0.41–1.17).
Objective response occurred in 39% of trebananib patients and 30% of placebo patients, including complete response in 4% and 5%. An interim overall survival analysis showed no significant difference between groups (median, 19.0 vs 17.3 months, HR = 0.86, P = .19).
Toxicity
The incidence of grade ≥ 3 adverse events was 56% in the trebananib group and 54% in the placebo group, including ascites in 11% vs 8%, neutropenia in 6% vs 9%, and abdominal pain in 5% vs 5%. Serious adverse events occurred in 34% vs 28% and adverse events leading to discontinuation of treatment occurred in 17% vs 6%. Edema of any grade occurred in 64% vs 28% (grade 3 in 5% vs 1%).
There was a difference between groups of < 2% in incidence of class-specific adverse events associated with anti-VEGF therapy, including hypertension, proteinuria, wound-healing complications, thrombotic events, and gastrointestinal perforation; bleeding of any grade was more common in the placebo group (10% vs 17%).
The investigators concluded, “Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent.”
Bradley J. Monk, MD, of the University of Arizona Cancer Center, Phoenix, is the corresponding author for The Lancet Oncology article.
The study was funded by Amgen. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
