In a phase III study (REGAL trial) reported in the Journal of Clinical Oncology, Tracy T. Batchelor, MD, MPH, of the Massachusetts General Hospital Cancer Center, and colleagues compared oral monotherapy with the investigational pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor cediranib and the combination of cediranib plus lomustine (CeeNu) vs a control arm of lomustine alone in patients with recurrent glioblastoma.1 There was no significant difference in progression-free or overall survival for either cediranib alone or cediranib/lomustine compared with lomustine alone.
In the trial, 325 patients aged 18 years or older with recurrent glioblastoma in whom prior radiation therapy and temozolomide had failed were randomly assigned in a 2:2:1 scheme 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). Enrollment was contingent on patients not having received prior anti-VEGF therapy. Other eligibility criteria included Karnofsky performance status ≥ 70, Mini-Mental Status Examination score ≥ 15, and life expectancy ≥12 weeks.
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 (ie, Karnofsky performance status = 90–100 in 50%, 51%, and 62.5%) or used corticosteroids at baseline (49%, 55%, and 40%).
The primary endpoint was progression-free survival, based on centralized, 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 therapy group (HR = 0.76, P = .16) vs 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 significant progression-free survival differences between the cediranib group and the combination group vs the lomustine group on either central review of postcontrast T1-weighted or noncontrast T2/fluid-attenuated inversion recovery MRI scans or local review of postcontrast T1-weighted MRI scans. Proportions of patients alive and progression-free at 6 months after randomization were 16% in the cediranib group, 35% in the combination group, and 25% in the lomustine group.
A total of 136 patients received postprogression therapy. The majority received bevacizumab (Avastin) alone or in combination, including 51% of combination patients, 51% of lomustine patients, and 27% of cediranib patients.
Secondary Efficacy Measures
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) vs the lomustine group (9.8 months). Predictive power calculations indicated that there was < 0.01% chance of concluding a positive outcome at the final overall survival analysis, and it was thus considered of no value to continue to final analysis.
There were no differences in the radiographic response rates between the two cediranib-containing groups. Best overall response rates were 15.3% in the cediranib group (including one complete response), 17.2% in the combination group (including two compete responses), and 8.9% in the lomustine group. Median changes in contrast-enhanced tumor area were –36% in the cediranib group, –28% in the combination group, and +14% in the lomustine group.
Clinical 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 each vs lomustine) and by increased time to deterioration in neurologic status in the cediranib group (HR = 0.82, P = .57) and the combination group (HR = 0.63, P = .01). There were no differences in time to deterioration of Karnofsky performance status for the cediranib group (HR = 1.03, 95% confidence interval [CI] = 0.65–1.62) or the combination group (HR = 0.73, 95% CI = 0.45–1.17) vs the lomustine group.
The most common adverse event was diarrhea (71% in cediranib group, 71% in combination group, and 19% in lomustine group). 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%). Other grade 3 or 4 adverse events occurring in at least 10% of any treatment group included fatigue (16%, 15%, and 9%), hypertension (14%, 6.5%, and 0%), and leukopenia (0.8%, 11%, and 5%). 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 end point of [progression-free survival] prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points 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). ■
Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit jco.ascopubs.org.
1. Batchelor TT, Mulholland P, Neyns B, et al: Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212-3218, 2013.