At the 2013 ASCO Annual Meeting, studies evaluating the addition of bevacizumab (Avastin) to standard therapy in newly diagnosed glioblastoma multiforme patients did not meet their primary endpoints. When paired with irinotecan, however, bevacizumab showed activity in MGMT-unmethylated tumors.

Bevacizumab plus Chemoradiotherapy

In a phase III study presented at the Plenary Session by Mark R. Gilbert, MD, Professor and Deputy Chair of Neuro-oncology at The University of Texas MD Anderson Cancer Center, Houston, bevacizumab added to the upfront standard of care failed to extend median overall survival. Although progression-free survival was improved in bevacizumab recipients, it did not meet the prespecified statistical target.¹

“Molecular profiling studies may uncover tumor subsets that identify patients benefiting from first-line bevacizumab, but until this subgroup has been defined, these results do not support the use of bevacizumab for newly diagnosed glioblastoma,” Dr. Gilbert said.

Based on bevacizumab’s activity in recurrent disease, the Radiation Therapy Oncology Group (RTOG) 0825 trial evaluated its first-line or early use in 637 newly diagnosed patients. Patients received chemoradiotherapy (temozolomide/radiotherapy→temozolomide; standard of care) plus placebo or chemoradiotherapy plus bevacizumab at 10 mg/kg every 2 weeks. Patients in the control arm could cross over to receive bevacizumab at disease progression, which 41% did.

Overall survival and progression-free survival were the co–primary endpoints of the study. The P values for statistical significance were .046 for overall survival and .004 for progression-free survival.

No Improvement in Co–Primary Endpoints

After a median follow-up of 20.5 months, median overall survival was 15.7 months with bevacizumab and 16.1 months with standard therapy (hazard ratio [HR] = 1.13; P = .021) and median progression-free survival was 10.7 and 7.3 months, respectively (HR = 0.79; P = .007).

A prespecified analysis of subgroups was performed based on MGMT promoter methylation and a 9-gene signature at baseline. Outcomes in the pooled treatment arms revealed interesting differences.

Median overall survival for patients with MGMT-methylated tumors was 23.2 months, compared with 14.3 months for MGMT-unmethylated status (HR for unmethylated/methylated = 2.10; P < .001). Median progression-free survival was 14.1 vs 8.2 months, respectively (HR for unmethylated/methylated = 1.67; P < .001).

The analysis did not identify a group of patients who derived benefit from first-line bevacizumab.

“There was no definable group with an overall survival benefit with bevacizumab,” Dr. Gilbert reported.

A number of patient-reported outcomes and measures of neurocognitive function worsened over time in the bevacizumab arm. “Symptom burden, neurocognitive function and quality-of-life data show an overall decline over time on first-line bevacizumab, possibly reflecting unrecognized tumor progression because of the effects of antiangiogenic treatment on brain tumor imaging,” he said. Adverse events, including hypertension, thrombosis, wound issues, bowel perforation, hemorrhage, and neutropenia, were more common with bevacizumab.

Predicting Response

Based on analysis of RTOG 0825 data, a correlative project called PRoB-GBM aimed to identify patients likely to respond to bevacizumab using molecular biomarkers. As reported by Erik P. Sulman, MD, PhD, Assistant Professor of Radiation Oncology at MD Anderson,² the researchers used residual tissue from the MGMT/molecular stratification portion of the study in 234 patients to build the predictive model, characterizing 71% of the samples as genetically “favorable” and 29% as “unfavorable.”

The upfront use of bevacizumab extended survival in patients with a PRoB-favorable molecular profile (20.3 months), compared to those with a PRoB-unfavorable profile (10.4 months)—a highly significant difference (P < .0001) that was not observed with standard therapy or with bevacizumab in the salvage setting.

AVAglio Study

Similar findings were reported by Roger Henriksson, MD, PhD, Head of Experimental Research at Umeå University in Sweden, for the AVAglio study (see additional perspective here), which had an identical study design and similar median overall survival (17 months in each arm) and median progression-free survival (10.6 months with bevacizumab vs 6.2 months with standard care, HR = 0.64, P < .0001).³

However, in AVAglio, health-related quality-of-life was improved for patients receiving bevacizumab, which differed from RTOG 0825. In AVAglio, this was measured using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30).

Bevacizumab/Irinotecan in MGMT-unmethylated Tumors

More encouraging results were reported for the phase II GLARIUS study, reported as a late-breaking abstract by Ulrich Herrlinger, MD, Professor of Clinical Neurooncology at the University of Bonn, Germany.⁴

In GLARIUS, 182 patients with MGMT-unmethylated glioblastoma received bevacizumab plus irinotecan or temozolomide, all given with radiation therapy at the standard dose for 6 weeks. Patients in the experimental arm received four cycles of bevacizumab over 6 weeks of radiation, then bevacizumab plus irinotecan every 2 weeks until progression. Patients in the temozolomide arm received six courses of temozolomide.

At 6 months, progression-free survival was significantly higher with bevacizumab/irinotecan: 9.74 vs 5.99 months (HR = 0.30; P < .0001). Overall survival, the secondary endpoint, was also significantly longer, in spite of a 63% crossover rate: 16.6 vs 14.8 months (HR = .60; P = .031). The experimental arm also required less steroid use, Dr. Herrlinger reported.

Patients in the experimental arm experienced more grade 3/4 vascular events, whereas those on temozolomide had more hematotoxicity. ■

Disclosure: Dr. Gilbert has a consultant/advisory role with and has received honoraria from EMD Serono, Genentech, Merck, and Novartis, as well as research funding from Genentech, GlaxoSmithKline, and Merck. Dr. Sulman has received honoraria from Merck. Dr. Henriksson is a consultant or advisor for Roche and has received honoraria from Roche. Dr. Herrlinger is a consultant or advisor for Roche and has received honoraria and research funding from Medac and Roche.

References

1. Gilbert MR, Dignam J, Won M, et al: RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab in patients with newly diagnosed glioblastoma. 2013 ASCO Annual Meeting. Abstract 1. Presented June 2, 2013.

2. Sulman EP, Won M, Blumenthal DT, et al: Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract LBA2010. Presented June 2, 2013.

3. Henriksson R, Bottomley A, Mason W, et al: Progression-free survival and health-related quality of life in AVAglio, a phase III study of bevacizumab, temozolomide and radiotherapy in newly diagnosed glioblastoma. 2013 ASCO Annual Meeting. Abstract 2005. Presented June 1, 2013.

4. Herrlinger U, Schaefer N, Steinbach JP, et al: Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: First results from the randomized multicenter GLARIUD trial. 2013 ASCO Annual Meeting. Abstract LBA2000. Presented June 1, 2013.