This article is more than 5 years old. Information may no longer be current.
Bevacizumab plus lomustine improved outcomes in recurrent glioblastoma
Click Here to Manage Email Alerts
The combination of lomustine plus bevacizumab induced higher OS rates than either agent alone, according to results of a randomized, open-label phase 2 trial.
Patients with recurrent glioblastoma have few treatment options, and second-line chemotherapy has demonstrated only modest anti-tumor activity. Bevacizumab (Avastin, Genentech) often is used in this patient population. However, well-controlled trials have not been conducted, and it was unclear if high response rates reported after bevacizumab treatment correlated with extended OS.
The current three-arm, multicenter trial include 140 patients who experienced a first recurrence of glioblastoma after chemotherapy with temozolomide (Temodar, Schering-Plough).
Researchers randomly assigned patients to 110 mg/m2 oral lomustine (Ceenu, Bristol-Myers Squibb) alone once every 6 weeks, 10 mg/kg bevacizumab IV alone once every 2 weeks, or combination treatment with both agents. OS at 9 months served as the primary outcome measure.
The first eight patients to complete two cycles of 6 weeks in the combination arm were included in a safety analysis. Three patients experienced grade 3 thrombocytopenia and two patients experienced grade 4 thrombocytopenia, which prompted reduction of bevacizumab dose intensity.
Researchers also reduced lomustine dosage to 90 mg/m2 in the combination arm only.
The final analysis included 50 patients assigned bevacizumab alone, 46 assigned lomustine alone, eight patients assigned to the original combination of bevacizumab plus 110 mg/m2 lomustine, and 44 assigned bevacizumab plus 90 mg/m2 lomustine.
At 9 months, researchers reported OS rates of 87% (95% CI, 39-98) among patients assigned bevacizumab plus 110 mg/m2 lomustine; 59% (95% CI, 43-72) among patients assigned combination therapy with bevacizumab plus 90 mg/m2 lomustine; 43% (95% CI, 29-59) among patients assigned lomustine alone; and 38% (95% CI, 25-51) among patients assigned bevacizumab alone.
The majority of patients (87%; n=129) discontinued treatment due to progressive disease. At the time of the analysis, 97% of patients died and 2% remained on treatment.
The higher rates of fatigue, infections and hypertension observed in the combination arm may be due to longer treatment duration in that group compared with single-agent groups, according to researchers. After the lomustine dose was reduced to 90 mg/m2, hematologic toxicities in the combination arm were similar to those observed with single-agent lomustine. All cases of hypertension were grade 3 and were well controlled with additional medication, researchers wrote.
“The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies,” the researchers wrote. “However, the results in the bevacizumab alone group do not justify further studies of this treatment.”
The potential benefit of the bevacizumab–lomustine combination raises questions about pharmacology and drug delivery, Mark R. Gilbert, MD, of the department of neuro-oncology at The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.
“Lomustine has been shown to have single-agent activity in recurrent glioblastoma, and nitrosoureas are well known to readily penetrate the blood–brain barrier,” Gilbert wrote. “Therefore, the failure of other agents, such as irinotecan, to show benefit in combination with bevacizumab might well be related to the decrease in blood–brain barrier permeability that is a known consequence of anti-angiogenic treatment. Future studies assessing treatment combinations with bevacizumab or other anti-angiogenic agents should either have strong preclinical in-vivo data indicating adequate drug delivery or data from comparable studies using imaging-based measures of drug delivery.”
The bevacizumab–lomustine combination also must be studied more extensively, Gilbert wrote.
“Although encouraging, unrecognized differences might have existed between the groups such that the apparent benefit of the combination regimen was caused by the random assignment of a group of patients with better prognosis,” he wrote. “Hence, we need a subsequent randomized phase 3 study that is adequately powered to definitively answer whether the combination of bevacizumab and lomustine provides a survival benefit and thus whether this treatment should be the standard of care for recurrent glioblastoma.”
For more information:
- Gilbert MR. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70329-8.
- Taal W. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70314-6.
Disclosure: The study was funded by Roche Nederland and KWF Kankerbestrijding. The researchers report consultant roles with AbbVie, Amgen, Celldex, Merck Ag and Roche; research funding from AbbVie and Roche; and speakers’ bureau roles with MSD.
Perspective
Back to Top
Ashley L. Sumrall, MD
Taal and colleagues attempt to move us one step forward in the discussion of a clinical question affecting all patients with glioblastoma: What do we do when the disease recurs? All tumors recur, and there is no true consensus as to which therapy is best suited for initial recurrence. Should we start bevacizumab at first recurrence or hold off? Should we treat with more alkylators?In this trial, patients were required to be at least 4 weeks free of chemotherapy. We do not have information as to how many prior cycles of temozolomide patients received prior to randomization. Could this affect their response to more alkylator therapy? Also, very few patients (10% to 13%) were managed with a second resection. New data encouraging evaluation for reoperation, where feasible, could impact interpretation of these findings.
Due to excessive hematotoxicity, lomustine was dose-reduced. Prior to this, some patients with thrombocytopenia received reduced-intensity bevacizumab dosing. Even with adjustments, a disappointing 34% of enrolled patients in the combination therapy arm received the planned six cycles. Reasons included toxicity and progression. PFS was modest for all groups. Despite this, the OS was encouraging.
It would be interesting to know more about the 19 patients who received sequential therapy (those who were on single-agent bevacizumab and crossed over to lomustine only). Did they have a similar OS benefit? Also, the impact of crossover and salvage regimens should always be considered. In this group, crossover to bevacizumab was not allowed, as it is not commercially available in the Netherlands. Salvage therapy varied per group but was surprisingly not standard-of-care for these patients. A mere 38% of patients on the combination arm received salvage of any type. The other subgroups hovered around 50%. With regard to survival data, this is markedly different than most studies we have conducted in the United States.
A phase 3 trial is planned and should help to delineate some of these issues. Patients and physicians both are anxious to move forward in this dilemma.
Click Here to Manage Email Alerts