The angiogenesis inhibitor trebananib failed to improve outcomes over placebo when combined with carboplatin and paclitaxel in patients with advanced ovarian cancer, according to a phase III trial. The agent did not introduce significant new safety signals, but the study suggests this combination has little activity in this setting.
The combination of carboplatin and paclitaxel remains the standard of care following surgery for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer. “Changes to the chemotherapy regimen, including the addition of targeted therapies, have had little success in improving overall survival,” wrote study authors led by Ignace Vergote, PhD, of the Leuven Cancer Institute in Belgium. “Therefore, there remains a substantial unmet need in first-line therapy for ovarian cancer.”
Inhibition of angiogenesis has shown some promise in ovarian cancer in the past. Trebananib inhibits angiopoietin 1 and 2 from binding with the tyrosine kinase receptor Tie 2, and in early-phase trials it showed encouraging antitumor activity. The new phase III trial included a total of 1,015 patients randomized to receive either trebananib (678 patients) or placebo (337 patients) along with carboplatin and paclitaxel; they were followed for a median of 27.4 months, and the results were published in Lancet Oncology.
Patients had a median age of 59 years in both groups, and over 80% of the cohort was white. The primary tumor type was ovarian cancer in 86% of both groups, followed by primary peritoneal in approximately 10%, and fallopian tube cancer in approximately 5%.
The median progression-free survival was 15.9 months with trebananib, compared with 15.0 months with placebo, for a hazard ratio (HR) of 0.93 (95% CI, 0.79–1.09). In prespecified subgroup analyses, there were no differences between the groups in patients with varying disease stage or residual tumor following surgery.
The overall survival data in the intention-to-treat population were not mature at the time of data cutoff, but the investigators provided an estimate. In that analysis, the median overall survival was 46.6 months with trebananib and 43.6 months with placebo, for an HR of 0.99 (95% CI, 0.79–1.25).
Almost all patients in both groups experienced at least one adverse event (AE). Serious AEs were reported in 40% of trebananib patients and in 31% of placebo patients, and grade 3 or worse AEs occurred in 76% and 71% of the groups, respectively. More patients discontinued trebananib treatment due to AEs (28% vs 13%).
“The results from this study showed that trebananib in combination with carboplatin plus paclitaxel as first-line treatment following primary debulking surgery or interval debulking surgery did not improve progression-free survival compared with placebo plus carboplatin plus paclitaxel,” the authors concluded, adding that quality of life was maintained with trebananib compared with placebo.
In an accompanying editorial, Angeles Alvarez Secord, MD, of the Duke Cancer Institute in Durham, North Carolina, noted that this study “continued to use a one-size-fits-all approach, despite data showing that ovarian cancer subtypes are molecularly distinct and, even within subtypes, have substantially different genomic profiles.” Furthering the field may require more adaptive trial approaches based on molecular or immunological characteristics. “Whether the promise of precision and personalized medicine in ovarian cancer will be realized or the one-size-fits-all approach will yield another negative result remains to be seen,” she wrote.