The February 20, 2014 issue of The New England Journal of Medicine features the results of two well-conducted, placebo-controlled, randomised trials: the Avastin in Glioblastoma (AVAglio) trial and the Radiation Therapy Oncology Group (RTOG) 0825 trial. Both studies address the clinical benefit of adding bevacizumab to the best standard treatment for newly-diagnosed glioblastoma (radiotherapy/temozolomide).The trials were nearly identical in design, patient characteristics, and the primary endpoints of progression-free survival (PFS) and overall survival (OS). Despite that, both show a prolongation of PFS with bevacizumab didn’t translate in significant effect on OS. The accompanying editorial tries to explain the possible reasons and states that the most obvious explanation is that nearly half the patients in the placebo group received bevacizumab at the time of recurrence, thereby potentially diluting a bevacizumab-mediated survival advantage.
Glioblastoma is the most common primary malignant adult brain tumour and, despite treatment advances in recent years, the average survival of patients enrolled in clinical trials is less than 16 months with few patients living beyond five years. Glioblastoma is characterised by angiogenesis. Interest in targeting angiogenesis in glioblastoma led to several phase II studies of bevacizumab, a humanised monoclonal antibody targeting vascular endothelial growth factor (VEGF), in patients with recurrent glioblastoma These early trials showed responses on magnetic resonance imaging (MRI) and, occasionally, clinical responses: a 35-40% objective response rate, or tumour shrinkage, of more than 50%, and a six-month PFS rate in the mid-30%. Based on these findings, in May 2009, the USA Food and Drug Administration (FDA) granted an accelerated approval of bevacizumab in the second-line setting.
However, concern soon arose over the true clinical benefit of bevacizumab, given the relatively short duration of response, and the possibility that much of the response seen on imaging could be a function of tumour-associated vascular stabilisation rather than a true antitumour effect, and the highly infiltrative pattern of recurrence in gliomas treated with bevacizumab. Before this trial, no randomised, double-blind studies with the drug in glioblastoma had been conducted.
The results of AVAglio study
In the AVAglio trial, the researchers randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab or placebo, plus radiotherapy and oral temozolomide for 6 weeks. After a 4-week treatment break, maintenance bevacizumab or placebo, plus temozolomide was continued for six 4-week cycles, followed by bevacizumab monotherapy or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary endpoints were investigator-assessed PFS and OS.
A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median PFS was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; p < 0.001). The benefit with respect to PFS was observed across subgroups. However, OS did not differ significantly between groups. The OS rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (p = 0.049) and 33.9% and 30.1% at 2 years.
Baseline health-related quality of life (QoL) and performance status (PS) were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).
The authors concluded that the addition of bevacizumab to radiotherapy/temozolomide did not improve survival in patients with newly diagnosed glioblastoma. Improved PFS and maintenance of baseline QoL and PFS were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.
The study was funded by F. Hoffmann–La Roche. The ClinicalTrials.gov number of the study is NCT00943826.
The first author of the study is Dr Olivier Chinot from Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Service de Neuro-Oncologie, Centre Hospitaliere Universitaire Timone, Marseille, France.
The results of RTOG 0825 study
In this randomised, double-blind, placebo-controlled trial, the investigators treated adult patients with centrally confirmed glioblastoma with radiotherapy and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary endpoints, with the addition of bevacizumab.
A total of 978 patients were registered, and 637 underwent randomisation. There was no significant difference in the duration of OS between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). However, the PFS was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79).
There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group.
Over time, an increased symptom burden, a worse QoL, and a decline in neurocognitive function were more frequent in the bevacizumab group.
The authors concluded that first-line use of bevacizumab did not improve OS in patients with newly diagnosed glioblastoma; PFS was prolonged but did not reach the prespecified improvement target.
The international RTOG 0825 study was a collaboration of three cooperative groups: RTOG, NCCTG and ECOG. The study was supported by grants (U10 CA21661 and U10 CA37422) from the National Cancer Institute (USA) and by an unrestricted educational grant from Genentech.
The ClinicalTrials.gov number is NCT00884741.
The study results were first presented on the plenary session of the 2013 Annual Meeting of the American Society of Clinical Oncology, Chicago (May 31–June 4).
The first author of the paper is Dr Mark Gilbert, principal study investigator and professor of neuro-oncology at the University of Texas MD Anderson Cancer Center in Houston. In a press release he said: "We postulated that patients with worse prognosis, determined by their tumor markers, would do better if they received bevacizumab as first-line treatment because they may not survive to take advantage of, or do well enough to be considered for, second-line treatment, but we didn't find that result".
Basically study participants were stratified equally across study arms by prognostic molecular markers of tumour O6-methylguanine–DNA methyltransferase (MGMT) methylation status and a tumour-based 9-gene assay. Investigators, however, did not find a subgroup of patients based on the molecular marker analysis who survived longer from first-line bevacizumab administration.
In addition, bevacizumab is known to confound MRI examination results used to assess tumour progression. RTOG 0825 investigators incorporated a "net clinical benefit" component in the trial design to determine if QoL, symptom burden and neurocognitive function test results corroborate MRI-reported stable or improved disease status. More than 80% of study participants agreed to take part in the net clinical benefits component, which demonstrated a greater decline of cognitive function for patients in the bevacizumab arm compared with those in the placebo arm.
"Study participants' consent allowing the collection of tumour tissue and blood samples, as well as imaging examination, longitudinal symptom, QOL, and neurocognitive function data provides RTOG investigators a rich archive of data to support ongoing investigations of potential molecular markers to identify subgroups of patients who may benefit from early bevacizumab," says study co-principal investigator Dr Minesh Mehta, chair of the RTOG Brain Tumor Committee and a professor of radiation oncology at the University of Maryland School of Medicine.
The unprecedented collection of specimens and associated outcome data will provide significant future information to investigate new treatment strategies for these patients within NRG Oncology. As of March 1, 2014, RTOG will join with the National Surgical Adjuvant Breast and Bowel Project and the Gynecologic Oncology Group to conduct cancer research as NRG Oncology, one of four adult cancer research groups conducting multi-institutional clinical trials within the USA NCI's National Clinical Trials Network.
Difference in patient-reported outcomes
Both, the AVAglio and the RTOG 0825, trials included patient-reported outcomes, such as QoL and results of neurocognitive testing, in their study design as secondary endpoints. However, the results diverge in their outcomes. Whereas the AVAglio trial showed improvement in or prolonged maintenance of QoL and PS, the RTOG 0825 trial showed a worsening of QoL and a decline in cognitive function. According to Dr Mehta, the cognitive decline observed in the RTOG 0825 study may have stemmed from unrecognised progression of the tumour, masked by the use of bevacizumab, or neurotoxicity related to the bevacizumab.
In the accompanying article, Dr Fine wrote that subtle differences in data acquisition, analytic methods, and extent of surgical resection could have influenced the data, but the true reason for the difference observed between studies remains unanswered. He advocates that the investigators should share raw data from their trials with each other and with independent investigators to try to resolve the question of the true effects of bevacizumab on patient-reported outcomes.
Future outlook
Dr Fine commented that it is worth noting that despite its limitations, bevacizumab remains the single most important therapeutic agent for glioblastoma since temozolomide. Future efforts should focus on identifying imaging markers and biomarkers that may be predictive of a response to bevacizumab. New and robust imaging and clinical endpoints need to be identified and incorporated into future clinical trials, given the complex effects of anti-VEGF agents in gliomas on MRI and the questionable usefulness of current patient-reported outcomes. Future trials of bevacizumab in glioblastoma will also need to explore its activity in combination with newer agents (e.g., c-Met inhibitors), given the increased tumour invasiveness seen with bevacizumab at the time of progression.
References
- Chinot OL, Wick W, Mason W, et al. Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma. N Engl J Med 2014; 370:709-722.
- Gilbert M, Dignam JJ, Armstrong TS, et al. A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma. N Engl J Med 2014; 370:699-708.
- Fine HA. Bevacizumab in Glioblastoma — Still Much to Learn. N Engl J Med 2014; 370:764-765.