Phase III Trial of Combination Therapy for Progressive Glioblastoma
In a phase III trial reported in The New England Journal of Medicine, Wick et al found that adding bevacizumab (Avastin) to lomustine at first disease progression did not improve overall survival in patients with progressive glioblastoma.
Study Details
In the trial, 437 patients with disease progression after chemoradiation from 38 sites in 8 countries were randomized 2:1 between November 2011 and December 2014 to receive bevacizumab at 10 mg/kg every 2 weeks plus lomustine at 90 mg/m2 every 6 weeks (n = 288) or lomustine at 110 mg/m2 every 6 weeks (n = 149). The primary endpoint was overall survival.
Overall Survival
The median number of treatment cycles was 1 (range 1–8) in the monotherapy group and 3 cycles each for lomustine (range = 1–8) and bevacizumab (range = 1–16) in the combination group, with the primary reason for stopping treatment being disease progression.
Median overall survival was 9.1 months in the bevacizumab group vs 8.6 months in the monotherapy group (hazard ratio [HR] = 0.95, P = .65). Median progression-free survival was 4.2 vs 1.5 months (HR = 0.49, P < .001). After disease progression, additional treatment was relieved by 53% of patients in the combination group and 66% in the monotherapy group.
MGMT promoter hypermethylation status was a significant prognostic factor in the study population; median progression-free survival was 5.7 months among 124 patients with methylated promoters vs 2.8 months among 146 with methylated promoters (HR = 0.37, 95% confidence interval = 0.29–0.49).
Adverse Events
Grade ≥ 3 adverse events occurred in 64% of patients in the combination group and 38% of the monotherapy group, including pulmonary embolism in 5% vs 0% and arterial hypertension in 24% vs 1%. Treatment-related serious adverse events occurred in 39% vs 10%. No benefit of bevacizumab was observed in health-related quality of life or neurocognitive function.
The investigators concluded: “Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma.”
The study was funded by the European Organisation for Research and Treatment of Cancer Research Fund and by F. Hoffmann–La Roche.
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