Bevaciziumab Fails To Boost OS For Progressive Glioblastoma

Adding bevacizumab to lomustine does not improve overall survival for patients with glioblastoma that has progressed after chemoradiation

medwireNews: A phase III trial has failed to demonstrate bevacizumab efficacy in patients with progressive glioblastoma, with no improvement in overall survival (OS) detected when the anti-angiogenic agent was given in combination with lomustine versus lomustine alone.

Although local progression-free survival (PFS) was “somewhat prolonged” with the combination regimen in the patients with first progression after chemoradiotherapy, the researchers report in The New England Journal of Medicine that the study did not confirm phase II data from the BELOB trial suggesting an OS advantage with bevacizumab plus lomustine.

Median OS was 9.1 months for the 288 patients randomly assigned to receive lomustine at a dose of 90 mg/m2 of body surface area every 6 weeks plus bevacizumab 10 mg/kg every 2 weeks.

This did not significantly differ from the median OS of 8.6 months for the 149 patients given lomustine only, at a dose of 110 mg/m2 every 6 weeks, say Wolfgang Wick, from the University of Heidelberg and German Cancer Research Center in Germany, and co-authors.

Local PFS was 4.2 months with the combination treatment versus 1.5 months for the monotherapy arm, giving a significant hazard ratio for disease progression or death of 0.49.

MGMT status was assessable for 270 patients, 45.9% of whom had promoter hypermethylation. MGMT methylation was associated with a longer PFS than unmethylated promoter patients and those with undetermined results (median 5.7 vs 2.8 and 3.0 months, respectively). Similarly, methylated MGMT status was associated with significantly longer OS compared with an unmethylated status, at a median of 13.5 versus 8.0 months.

But analysis indicated that PFS, but not OS, was found to be longer in the combination group than the monotherapy arm, regardless of MGMT status.

“Earlier data suggested that lomustine had little effect on MGMT unmethylated glioblastomas, and adding bevacizumab did not alter this conclusion”, the researchers remark.

Furthermore, patients given lomustine plus bevacizumab were significantly more likely to experience grade 3–5 adverse events than controls, at 63.6% versus 38.1%, most commonly haematological toxicity in both arms (53.7 vs 49.7%).

Serious treatment-related events occurred in 38.5% versus 9.5% of these groups. There were five deaths in the combination arm (two cases of myocardial infarction and one each from large intestine perforation, sepsis and intracranial haemorrhage) and one lung infection death in the control arm.

“Although important given the lack of overall survival benefit, the higher numbers of adverse effects should be assessed relative to the longer treatment period in the combination group”, the investigators caution, noting that the combination group underwent a median three cycles of both lomustine and bevacizumab versus one cycle in the monotherapy arm.

They note that health-related quality of life did not significantly differ between the treatment arms until week 36, when monotherapy was associated with improvements in social functioning (versus stable functioning in the combined group) and better global health status.

And there were no differences in neurocognitive function between the treatment arms at the baseline or follow-up assessments, the team adds.

Reference

Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017; 377: 1954–1963. DOI: 10.1056/NEJMoa1707358

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