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Investigational fusion protein plus paclitaxel shows promise in ovarian cancer
Karlan BY. J Clin Oncol. 2012;30:362-371.
Favorable efficacy and toxicity outcomes were observed in patients with ovarian cancer assigned to the investigational protein AMG 386 plus weekly paclitaxel, according to recent results.
The researchers examined AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, as a possible therapeutic option for ovarian cancer.
The aim of the trial was to examine the efficacy and toxicity of AMG 386 plus weekly paclitaxel in 161 patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. The primary outcome measure was PFS. Secondary endpoints included OS, objective response, CA-125 response, safety and pharmacokinetics, according to the results.
Eligible patients were randomly assigned to one of three treatment regimens in a 1:1:1 ratio: paclitaxel (80 mg/m2 once weekly for 3 weeks on and 1 week off) plus IV AMG 386 10 mg/kg once weekly; AMG 386 3 mg/kg once weekly; or placebo once weekly.
Patients in the combination therapy group achieved a median PFS of 7.2 months (95% CI, 5.3-8.1) compared with 5.7 months (95% CI, 4.6-8) in the AMG 386 group and 4.6 months (95% CI, 1.9-6.7) in the placebo group.
The HR for the two treatment groups combined compared with the placebo group was 0.76 (95% CI, 0.52-1.12).
The researchers highlighted an exploratory dose-response rate for PFS across the three arms of the trial (Tarone’s test; P=.037).
Combination therapy was linked to an objective response rate of 37% compared with 19% for AMG 386 alone and 27% for placebo.
Grade-3 or higher adverse events were reported in 65% of patients in the combination group, 55% of patients in the AMG 386 group and 64% of patients who received placebo.
Hypertension was reported at rates of 8% in the combination group, 6% in the AMG 386 group and 5% in the placebo group. Seventy-one percent of patients in the combination arm experienced peripheral edema vs. 51% in the AMG 386 group and 22% in the placebo group. Hypokalemia was reported in 21% of patients assigned to the combination, 15% of patients assigned to the study drug alone and 5% of patients assigned to placebo.
Linear pharmacokinetic properties at the tested doses were demonstrated by the study drug.
“AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile,” the researchers wrote. “The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.”
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As emphasized in the companion editorial to this positive randomized phase 2 study, VEGF is not the only “druggable” driver of angiogenesis in epithelial ovarian cancer. Angiopoietin-1 and -2 can be inactivated with AMG 386 and, importantly, the side effect profile is nothing like anti-VEGF agents such as bevacizumab (Avastin, Genentech). Bowel perforation, hypertension and proteinuria are not seen. The strength of this trial was that it was placebo-controlled. PFS is only an appropriate measure of clinical benefit when measured correctly. Based on the encouraging results of the Karlan trial, three randomized phase 3 Trials in Ovarian Cancer (TRINOVA) have been initiated. TRINOVA-1 is identical to the Karlan study. TRINOVA-2 uses a chemotherapy backbone of pegylated liposomal doxorubicin in recurrent ovarian cancer after failing up to three prior regimens. TRINOVA-3 is a frontline, randomized, phase 3 trial.
– Bradley J. Monk, MD, FACS, FACOG
Professor and director of the
division of gynecologic oncology
Creighton University School of Medicine
St. Joseph’s Hospital and Medical Center, Phoenix
Disclosure: Dr. Monk reports no relevant financial disclosures.
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