This non-VEGF antiangiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents.
—Bradley J. Monk, MD, and colleagues
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.
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).
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%).
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.
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.
Production of vascular endothelial growth factor (VEGF) is increased during normal ovulation, and can account for much of the reversible toxicity associated with ovarian hyperstimulation.1,2 We also have compelling data from multiple clinical trials to validate the importance of tumor-associated...