No Progression-Free Survival Difference for Cediranib or Cediranib/Lomustine vs Lomustine in Recurrent Glioblastoma
In a phase III study (REGAL trial) reported in Journal of Clinical Oncology, Tracy T. Batchelor, MD, MPH, of Massachusetts General Hospital, and colleagues compared oral monotherapy with the pan-VEGF tyrosine kinase inhibitor cediranib and the combination of cediranib plus lomustine (CeeNu) vs lomustine alone in patients with recurrent glioblastoma. There was no significant difference in progression-free survival for either cediranib alone or cediranib/lomustine compared with lomustine alone.
Study Details
In the trial, 325 patients with recurrent glioblastoma who had received radiation therapy and temozolomide were randomly assigned to cediranib at 30 mg/d (n = 131), cediranib at 20 mg/d plus lomustine at 110 mg/m2 once every 6 weeks (n = 129), or lomustine plus placebo (n = 65). Patients could not have received anti-VEGF therapy or cranial radiation within 3 months before study entry. The cediranib, cediranib/lomustine, and lomustine groups were well matched for age (median, 54 years in all groups) and resection for recurrent disease (38%, 38%, and 37%), but fewer patients in the lomustine group had Karnofsky performance status of 80 or less (50%, 48.8%, and 37.8%) and used corticosteroids at baseline (49%, 55%, and 40%), and more patients in the combination group had their last radiotherapy at greater than 12 months prior to randomization (34%, 42%, and 34%). The primary endpoint was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans.
Progression-Free Survival Outcomes
There was no significant difference in progression-free survival for the cediranib group (hazard ratio [HR] = 1.05, P = .90) or the combination group (HR = 0.76, P = .16) compared with the lomustine group. Median progression-free survival was 92 days (1st quartile, 80 days; 3rd quartile, 128 days) in the cediranib group, 125 days (1st quartile, 83 days; 3rd quartile, 201 days) in the combination group, and 82 days (1st quartile, 42 days; 3rd quartile, 168 days) in the lomustine group. There were no differences in median overall survival between the cediranib group (8.0 months, HR = 1.43, P = .10) or the combination group (9.4 months, HR = 1.15, P = .50) and the lomustine group (9.8 months).
Activity of cediranib was suggested by greater reduction in mean corticosteroid use in the cediranib group (–26%) and combination group (–23%) compared with the lomustine group (+5%; P = .01 for both vs lomustine) and by increased time to deterioration in neurologic status in the cediranib (HR = 0.82, P = .57) and the combination group (HR = 0.63, P = .01).
Toxicity
The most common adverse event was diarrhea (71%, 71%, and 19%). Adverse events of grade 3 or higher were more common in the combination group (61%, 80%, and 61%), including thrombocytopenia (2%, 38%, and 22%) and neutropenia (1%, 20%, and 3%). Serious adverse events occurred in 43%, 37%, and 41% of patients, respectively, and adverse events led to discontinuation of cediranib or placebo in 15%, 18%, and 16% of patients, respectively.
The investigators concluded, “This study did not meet its primary endpoint of [progression-free survival] prolongation with cediranib either as monotherapy or in combination with lomustine [vs] lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary endpoints including time to deterioration in neurologic status and corticosteroid-sparing effects.”
They noted that since preclinical models suggest synergistic activity of anti-VEGF therapy and radiation therapy, cediranib in combination with chemoradiotherapy is being studied in phase II trials in patients with newly diagnosed glioblastoma (NCT00662506 and NCT01062425).
The study was supported by AstraZeneca.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
