AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.
Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.
Sara Freeman/IMNG Medical Media
Dr. Roger Stupp
Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.
CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.
The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m2 of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m2 for six cycles).
Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).
Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).
Sara Freeman/IMNG Medical Media
Dr. Michael Brada
Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.
"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.
Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.
Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).
The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.