A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma

Abstract

Background Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Methods Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m2). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. Results For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI: 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI: 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI: 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI: 2.5-6.01, p = 0.08). Conclusions The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

Therapeutic options in recurrent glioblastoma—An update

“…Another randomized phase II trial evaluated the combination of lomustine with 90 mg/m 2 with bevacizumab 5 mg/kg every 3 weeks versus bevacizumab alone at 10 mg/kg every 2 weeks in a heterogenous cohort of patients with glioblastoma at 1 st , 2 nd or 3 rd relapse. The authors emphasized a benefit for the subgroup of patients at 1 st relapse in the combination arm with a median OS with 13.1 months versus 8.8 months in the monotherapy arm without disclosing the number of patients in this subgroup and without reporting PFS and OS results of the intent-to-treat population [58]. Another phase II study evaluated the combination of nitrosourea, namely fotemustine with bevacizumab, however, not in a randomized but single-arm design [59].…”

“…In Europe, approval was refused because of the lack of a bevacizumab-free control arm. There are 9 phase II trials with a bevacizumab monotherapy arm, 3 of them single-arm studies [86][87][88], 5 trials compared bevacizumab with bevacizumab plus another agent, such as irinotecan [85], carboplatin [84], the histone-deacetylase inhibitor vorinostat [89], the multikinase inhibitor dasatinib [90] or lomustine [58]. Only one trial had a bevacizumab-free control arm with lomustine [54].…”

“…Only one trial had a bevacizumab-free control arm with lomustine [54]. Most of these trials used bevacizumab at 10 mg/kg IV every 2 weeks except one study with 15 mg/kg IV every 3 weeks [87] and one study with 5 mg/kg IV every 3 weeks when combined with lomustine [58]. Toxicity of bevacizumab was mainly non-hematologic including hypertension, thrombembolic events, fatigue, and impaired wound healing.…”

“…Surprisingly, the combination of bevacizumab with TMZ [72][73][74][75] seems less promising than the combination with nitrosoureas [54,58,59]. However, no direct comparisons are available and the trials evaluating bevacizumab plus temozolomide were conducted in part in highly pretreated patient populations [72][73][74].…”

New Directions in Anti-Angiogenic Therapy for Glioblastoma

“…Retrospective data suggest that the treatment of patients with high-grade glioma with low doses of bevacizumab (5 mg/kg per week or 7.5 mg/kg every 3−4 weeks) may be superior to standard dosing, potentially due to vascular normalization at lower doses [140,141]. A recent randomized phase 2 trial comparing low dose bevacizumab plus lomustine to standard dose bevacizumab monotherapy in recurrent GBM showed no difference in the primary endpoint of PFS (4.34 months for the combination arm versus 4.11 months for bevacizumab monotherapy, p = 0.19) [142]. However, there was a trend toward improved median PFS in patients with first recurrence.…”