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 vascular endothelial growth factor (VEGF) inhibitors and that involves a different signaling pathway. In the phase III TRINOVA-1 trial reported in Lancet Oncology, Bradley J. Monk, MD, of the University of Arizona Cancer Center, Phoenix, and colleagues found that adding trebananib to paclitaxel significantly prolonged progression-free survival in patients with recurrent epithelial ovarian cancer.¹ The toxicity profile of trebananib did not include an excess frequency of adverse events typically 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 IV placebo (n = 458) or trebananib at 15 mg/kg (n = 461). Patients had to have received one platinum-based regimen for primary disease and no more than two additional cytotoxic regimens for recurrent or persistent disease, had to have 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%), and histologic grade (eg, poorly differentiated in 59% and 56%, moderately differentiated in 15% and 18%).

The two groups were also balanced for 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 a 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). Hazard ratios favored trebananib treatment in all prespecified subgroups and significantly favored trebananib for subgroups with no previous angiogenic therapy (0.67), white (0.65) and Asian (0.62) ethnicity, 1 (0.75) and 2 (0.54) previous lines of therapy, platinum-free interval of ≤ 6 (0.65) and > 6 to 12 (0.66) months, no bulky disease (0.66), and age < 70 years (0.65). 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 recipients and 30% of placebo recipients, 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, with the most common in trebananib-treated patients being ascites (11% vs 8%), neutropenia (6% vs 9%), abdominal pain (5% vs 5%), localized edema (5% vs 1%), and hypokalemia (5% vs 3%). Serious adverse events occurred in 34% vs 28%, and adverse events led to discontinuation of treatment in 17% vs 6%.

Edema of any grade occurred in 64% vs 28% (grade 3 in 5% vs 1%). Other adverse events of any grade occurring in ≥ 10% of patients in either group and in ≥ 5% more patients in the trebananib group were ascites (20% vs 12%), pleural effusion (14% vs 4%), nasopharyngitis (12% vs 6%), and generalized edema (11% vs 3%), whereas those occurring in ≥ 5% more patients in the placebo group were neutropenia (28% vs 22%) and anemia (20% vs 10%).

Anti-VEGF Toxicities

Adverse events of interest on the basis of their association with anti-VEGF therapy did not appear to occur with markedly greater frequency in the trebananib group, including hypertension (6% vs 4%), bleeding (10% vs 17%), pulmonary embolism (1% vs 2%), arterial thrombotic events (1% vs 1%), proteinuria (3% vs 3%), impaired wound healing (< 1% vs < 1%), gastrointestinal perforation (2% vs < 1%), and venous thromboembolic events (6% vs 4%).

Assessment of patient-reported outcomes with the Functional Assessment of Cancer Therapy–Ovary questionnaire and its ovarian cancer–specific subscale and assessment of health utility with the EuroQol EQ-5D suggested no differences between the trebananib and placebo groups.

The investigators concluded:

Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF antiangiogenesis 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. ■

Disclosure: The study was funded by Amgen. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Monk BJ, Poveda A, Vergote I, et al: Antiangiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): A randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15:799-808, 2014.