Low-dose bevacizumab combined with lomustine has no significant effect on progression-free survival (PFS) or overall survival (OS) compared with standard-dose bevacizumab alone in patients with recurrent glioblastoma, according to results from a randomized phase II study.
In a subgroup of patients at first recurrence, the combination of low-dose bevacizumab plus lomustine showed a strong trend toward improvement in PFS compared with standard-dose bevacizumab, which supports the results from a prior clinical trial known as BELOB, which employed standard-dose bevacizumab combined with lomustine in patients with recurrent glioblastoma, according to presenting author Shiao-Pei S. Weathers, MD, at the 2015 ASCO Annual Meeting.
Nevertheless, use of low-dose bevacizumab does not appear to delay or prevent resistance to lomustine, according to Weathers, assistant professor, Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, Houston. High-dose bevacizumab leads to hypoxia, necrosis, and transformation to a more aggressive phenotype, and the hope was that using a low dose would delay hypoxia, thereby improving oxygenation and drug delivery, translating into improved clinical outcomes.
“Tumor hypoxia is a well-known mediator of treatment resistance and promotion or transformation to a more aggressive phenotype of glioblastoma,” said Weathers.
Bevacizumab received accelerated approval from the US Food and Drug Administration (FDA) in 2009, following the results of a phase II trial showing PFS improvement in patients who received bevacizumab for recurrent glioblastoma compared with historical controls. The long-term survival benefit associated with bevacizumab, however, has been disappointing, she pointed out. As monotherapy, the median duration of response is approximately 4 months.
In the up-front setting, bevacizumab did not result in an improvement in OS in two large randomized phase III trials.
Attention then shifted to combining bevacizumab with cytotoxic chemotherapy in the hopes that combination therapy might result in a survival benefit, said Weathers. The first study to explore combination therapy in an effort to prolong therapeutic efficacy was BELOB, a multi-institutional phase II trial that examined the standard-dose bevacizumab combined with lomustine in recurrent glioblastoma. The dosing and frequency of bevacizumab used in BELOB was 10 mg/kg every 2 weeks, the schedule that was granted FDA approval based on bevacizumab’s efficacy in treating solid tumors, such as colorectal cancer and nonsmall cell lung cancer.
The phase II study presented here was performed exclusively at MD Anderson Cancer Center. Patients with recurrent glioblastoma at either first, second, or third relapse were recruited, and randomized in a 1:1 fashion to bevacizumab, 5 mg/kg every 3 weeks, plus lomustine, 90 mg/m2every 6 weeks, or bevacizumab, 10 mg/kg every 2 weeks. The primary endpoint was PFS.
Of 83 patients enrolled, 71 met eligibility criteria and were randomized to one of the two treatment arms. Sixty-nine patients were evaluable for both efficacy and toxicity. The trial was terminated early for futility for the primary endpoint.
Low-dose bevacizumab plus lomustine was safe, but due to a number of grade-3 and grade-4 toxic events, particularly myelotoxicity, the protocol was amended to reduce the dose of lomustine to 75 mg/m2, following which the rate of grade 3/4 toxicities declined.
There was no statistically significant difference between the two treatment arms on median PFS4.9 months in the combination arm versus 3.1 months for bevacizumab alone (P= .05). A blinded radiology evaluation similarly found no significant difference in median PFS (P= .19).
Among patients with first recurrence only, median PFS was 6.4 months with low-dose bevacizumab plus lomustine compared with 3.1 months with standard-dose bevacizumab, which did not achieve significance (P= .41). Blinded radiology evaluation in this patient subgroup showed a strong trend favoring the combination arm over bevacizumab monotherapy on median PFS (5.0 months vs. 3.2 months;P= .08).
Median OS was a secondary endpoint. There was no significant difference on this endpoint between the combination and standard-dose bevacizumab (9.6 months vs 8.3 months;P= .75), which was also true in the subgroup with first recurrence only (13.1 months vs 8.8 months;P= .98).
Nine patients who progressed on bevacizumab alone crossed over to low-dose bevacizumab plus lomustine. There was no significant difference in median PFS between the two treatment arms when accounting for crossovers.
Blood and biomarker evaluations are ongoing.
Weathers S-PS, Han SX, Liu DD, et al. A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.J Clin Oncol2015;33 (suppl; abstr 2005).