Trebananib Improves Progression-Free Survival in Recurrent Ovarian Cancer


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Trebananib, an investigational antiangiogenesis inhibitor with a different mechanism of action than bevacizumab (Avastin), significantly improved progression-free survival in recurrent platinum-resistant and partially platinum-sensitive ovarian cancer in the phase III TRINOVA-1 trial. The addition of trebananib to paclitaxel prolonged the time to disease progression or death by 52% compared with paclitaxel plus placebo (P < .001), said Bradley J. Monk, MD, FACOG, FACS, of Creighton University School of Medicine and The University of Arizona Cancer Center, Phoenix, at the recent European Cancer Congress in Amsterdam.1

“Angiogenesis is a valid target in ovarian cancer. A long list of studies shows that antiangiogenesis agents can prolong progression-free survival in the platinum-sensitive space. However, no increase in overall survival has been seen with this approach,” he said.

Anti–vascular endothelial growth factor (VEGF) therapy with bevacizumab and pazopanib (Votrient) “creates a constellation of adverse events,” Dr. Monk continued. “The idea of the TRINOVA series of clinical trials is to target non-VEGF angiogenesis factors—angiopoeitin-1 and angiopoetin-2—with trebananib and determine efficacy and side effects with this non-VEGF approach,” he explained. Previous studies had suggested that inhibition of angiopoietin-1 and -2 with trebananib can delay progression of tumors or shrink them, he noted.

Study Design and Results

The phase III TRINOVA-1 trial enrolled 919 women with recurrent epithelial ovararian cancer and randomly assigned them to treatment with trebananib at 15 mg/kg IV every 4 weeks plus weekly paclitaxel or placebo plus weekly paclitaxel. Treatment continued until disease progression, toxicity, or withdrawal of consent.

Patients were stratified according to progression-free interval, measurable disease, and geographic region. At baseline, patients had received up to three prior cytotoxic regimens and had a progression-free interval of less than 12 months from the last treatment. About 40% of patients experienced treatment failure on one prior regimen, 40% on two, and 20% on three.

“This was a rigorous, closely audited clinical trial, with 919 patients from 179 sites in 32 countries. Today, I will present primary progression-free survival and interim overall survival results, and next year, the final overall survival,” Dr. Monk told listeners.

At a median follow-up of 10 months, median progression-free survival was 7.2 months in the trebananib group and 5.4 months for placebo (hazard ratio = 0.66, 95% confidence interval = 0.56–0.76, P < .001).

A prespecified subgroup analysis found that trebananib improved progression-free survival in all subgroups. Overall response rate was 38% with trebananib vs 30% with placebo. Dr. Monk noted that most responses were partial.

Adverse Events

The rate of adverse events of any grade was similar between the two treatment arms: 96% for trebananib and 97% for placebo, suggesting that trebananib does not increase toxicity when added to paclitaxel. The major toxicity of trebananib was edema, which occurred in 57% vs 26% of the two arms, respectively. Very few grade 3 or higher adverse events were reported with trebananib.

“The adverse event profile of antiangiopoietin therapy is not the same as with VEGF inhibitors,” Dr. Monk said. No increase in VEGF-associated side effects (ie, hypertension, proteinuria, wound healing complications, or arterial thrombotic events) was seen with trebananib.

Neutropenia and anemia were more common among placebo recipients, and neurotoxicity was more common among trebananib recipients, which appears to be related to a greater number of paclitaxel cycles in that arm, he said.

Other Major Results

The interim overall survival analysis showed a difference of approximately 2 months favoring trebananib (19 vs 17.3 months, respectively), but Dr. Monk cautioned that this is with only half (n = 313) of the expected survival events occurring.

TRINOVA-1 incorporated patient-reported outcomes using three different quality-of-life questionnaires: Functional Assessment of Cancer Therapy–Ovarian (FACT-O), the FACT ovarian cancer subscale (OCS), and the EuroQol Group’s EQ-5D. On these measures, no quality-of-life differences were reported between the two treatment arms.

Amgen is moving forward with a full development program for trebananib, Dr. Monk noted. ■

Disclosure: Dr. Monk reported no potential conflicts of interest.

Reference

1. Monk BJ, Poveda A, Vergote I, et al: A phase III, randomized, double-blind trial of weekly paclitaxel plus the angiopoeitin 1 and 2 inhibitor, trebananib, or placebo in women with recurrent ovarian cancer: TRINOVA-1. European Cancer Congress. Abstract 41. Presented October 1, 2013.


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