Adding Lomustine to Bevacizumab Improves Outcomes in Recurrent Glioblastoma

Martin J. Van Den Bent, MD

The combination of bevacizumab and lomustine showed superior efficacy compared with either agent alone in patients with recurrent glioblastoma, warranting further study, according to the phase II BELOB study presented by Martin van den Bent, MD, at the 2014 Society for Neuro-Oncology’s (SNO) Annual Meeting in Miami.

It is crucial to research recurrent glioblastoma treatments because of a scarcity of available choices, “There are only a few modestly active chemotherapy options in recurrent glioblastoma,” van den Bent, from the Erasmus MC Cancer Institute in Rotterdam, Netherlands, said. Although bevacizumab is approved as a second-line treatment for glioblastoma, this approval was based on an open-label study. At this point, there are few well-controlled randomized studies to support its use for recurrent glioblastoma, van den Bent noted.

In the phase II multicenter BELOB trial, 148 patients were assigned to bevacizumab at 10 mg/kg on days 1, 15, and 29, bevacizumab at 10 mg/kg on day 1, 15, and 29 in combination with lomustine orally on day 1 (90 mg/m²), or lomustine only orally at 110 mg/m² on day 1, in a 6-week cycle.

Earlier in the trial, a preplanned safety review led to the reduction of the lomustine dose in the combination arm to 90 mg/m², van den Bent said. The dose was lowered because of hematological-related adverse events. Subsequently, 8 patients were treated with bevacizumab plus lomustine at 110 mg/m² and 44 patients were treated at the 90-mg/m² dose.

Patients in the study were enrolled between December 2009 and November 2011 and had histologically proven glioblastoma, a first recurrence after chemoradiation with temozolomide, and had finished radiotherapy more than 3 months before entering the study. Patients had adequate bone marrow, renal, and hepatic function. The median age was 57 years and the median World Health Organization performance status was 1. The trial’s primary endpoint was 9-month overall survival (OS).

At the analysis, 130 patients were reviewed for a response. The 9-month OS was 43% in the lomustine arm, 38% in the bevacizumab arm, and 59% in patients who received both agents. The investigator-assessed objective response rate was 5% in the lomustine arm, 38% in the bevacizumab arm, and 34% in the bevacizumab/lomustine arm.

The results do not support a continuation of treatment with bevacizumab alone. “There was a high response rate to single-agent bevacizumab, but it didn’t translate into overall survival,” van den Bent said.

Hypertension was the most frequently reported toxicity (26% of bevacizumab patients, 7% of lomustine patients, and 25% of bevacizumab and lomustine patients). Other commonly reported toxicities included fatigue (4%, 9%, and 18%, respectively) and infections (6%, 4%, and 11%, respectively). When BELOB trial results were reported in Lancet Oncology earlier this year, 97% of patients had died, and 2% remained on treatment.

In secondary analyses, researchers found isocitrate dehydrogenase 1 (IDH1) mutations in 8 patients. Progression-free survival and OS were longer in patients with IDH1 mutations compared with wild-type mutations. The 9-month OS was 60% for patients with the IDH1 mutation in the combination arm. Additionally, the MGMT promoter was methylated in 47% of patients and also indicated better responses. Researchers suggest that patients with IDH mutations should be assessed in separate clinical trials and should even be excluded from trials in the recurrent setting, due to the inherently better outcomes seen.

Findings from the phase II BELOB trial met prespecified criteria for the establishment of a phase III trial. The combination of bevacizumab and lomustine are being studied in the randomized, controlled phase III study EORTC trial 26101 trial, with results expected by next year’s SNO meeting, van den Bent said.

Reference

Taal W, OOsterkamp H, Walenkamp A, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncology. 2014:15:943 — 953.

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