Given the results of the AVAglio trial, we feel that a more balanced discussion about the role of bevacizumab (Avastin) in patients with newly diagnosed glioblastoma is in order. The accompanying article in The ASCO Post suggests that bevacizumab has no benefit in newly diagnosed glioblastoma; data reported at ASCO by Henriksson et al1 and Wick et al2 have, however, highlighted the benefits of the combination of bevacizumab plus standard of care in this disease. We have summarized the key data below.
Progression-free Survival
We would first like to underline that AVAglio was a large phase III registration trial, including more than 920 patients worldwide, which assessed the benefit of adding bevacizumab to standard of care in the first-line treatment of patients with glioblastoma. The co-primary endpoints of AVAglio were investigator-assessed progression-free survival and overall survival. The trial was to be considered positive if the criteria for either one of thse endpoints were met.
The progression-free survival co-primary endpoint was met, with a statistically significant and clinically meaningful improvement in progression-free survival reported in the bevacizumab arm (bevacizumab plus standard of care) compared with the placebo arm (placebo plus standard of care), with medians of of 10.6 vs 6.2 months (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.55–0.74, P < .0001).2,3
Quality of Life
AVAglio also reported further measures of clinical benefit with bevacizumab. The importance of health-related quality of life for glioblastoma therapy was acknowledged by the AVAglio study investigators, and accordingly health-related quality of life assessment was included as a mandatory secondary endpoint in this study. Compliance with health-related quality of life questionnaires was high in this study, compared with other studies in glioblastoma.
The prespecified primary health-related quality of life analysis demonstrated significantly longer deterioration-free survival in global health status, physical functioning, social functioning, motor dysfunction, and communication deficit for patients receiving bevacizumab plus standard of care vs placebo plus standard of care.1 Additional comprehensive post-hoc analyses were consistent with the conclusion that patients treated with bevacizumab plus standard of care had maintained health-related quality of life during their progression-free time.1
Other Endpoints
Bevacizumab-treated patients also had a longer time to deterioration in Karnofsky performance status (HR = 0.65, 95% CI = 0.56–0.75, P < .0001) and a longer time during which a Karnofsky performance status ≥ 70 was maintained (9 vs 6 months), indicating that these patients were able to maintain functional independence for longer during their progression-free time, compared with their counterparts in the placebo arm.1 Maintained functional independence is considered an important treatment goal in glioblastoma therapy.
The AVAglio study also assessed corticosteroid use as a measure of clinical benefit. The negative effects of corticosteroid use on neurocognitive function and quality of life are well documented. In AVAglio, more patients in the bevacizumab arm than placebo arm (66 vs 47%, respectively) were able to discontinue corticosteroid use if they were taking corticosteroids at baseline. For patients off corticosteroids at baseline, those in the bevacizumab arm had a longer time to steroid initiation compared with those in the placebo arm (HR = 0.71, 95% CI = 0.57–0.88, P = .0018, 12.3 vs 3.7 months, respectively).1
Based on these data, we conclude that the addition of bevacizumab to standard of care can extend progression-free survival, as well as providing a meaningful clinical benefit as measured by health-related quality of life, functional status, and corticosteroid requirements.
Study Differences
There are differences between the Radiation Therapy Oncology Group (RTOG) 0825 trial and the AVAglio study that should be acknowledged. The progression-free survival was significant in AVAglio, but not in the RTOG 0825 trial. The discrepancy between the two studies may be related to the statistical plan, the methodology, and/or the interpretation of the data. The health-related quality of life analysis for AVAglio also yielded contrasting results, despite using tools similar to those in RTOG 0825 (EORTC Quality of Life Questionnaires, QLQ-C30, and BN20).
We observed that health-related quality of life was maintained for a longer duration in the bevacizumab arm, without any detrimental effect of bevacizumab, and we believe these results are reinforced by the high quality of the data collected in AVAglio, partly due to an outstanding compliance with the questionnaires throughout treatment.
Conclusions
In the context of this debilitating disease, which has seen no improvements in therapy since 2005 despite the evaluation of numerous promising treatments, we believe (in agreement with ASCO discussant Howard A. Fine, MD (see Expert Point of View here), that bevacizumab currently represents the single most important therapeutic agent for glioblastoma aside from the standard of care. Moreover, according to the new data from RTOG 0825 and AVAglio, which do not concern recurrent therapy, bevacizumab may be useful in the upfront setting. ■
Dr. Henriksson is Head of the Regional Cancer Center, Stockholm, and Head of Experimental Research at Umeå University, Sweden; Dr. Mason is a medical oncologist in the Brain Tumour Clinic at Princess Margaret Hospital, Toronto, Ontario, Canada; Dr. Chinot is Head of the Neuro-Oncology Department at Aix-Marseille University, Marseille, France; and Dr. Wick is Chairman of Neuro-Oncology and Director of the National Tumor Center at the University of Heidelberg, Germany.
Disclosure: Dr. Henriksson has received compensation for serving on the steering committee for this trial from F. Hoffmann-La Roche. Dr. Mason has acted as a consultant for F. Hoffmann-La Roche and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche. Dr. Chinot has received honoraria from F. Hoffmann-La Roche, AstraZeneca, and MSD, acted as a consultant for F. Hoffmann-La Roche, received research support from F. Hoffmann-La Roche and Schering–Plough, and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche. Dr. Wick has acted as a consultant for F. Hoffmann-La Roche and Eli Lilly, received research support from Boehringer Ingelheim, Alogenix, and MSD, and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche.
References
1. Henriksson R, Bottomley A, Mason W, et al: Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract 2005. Presented June 1, 2013.
2. Wick W, Cloughesy TF, Nishikawa R, et al: Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract 2002. Presented June 1, 2013.
3. Chinot O, Wick W, Mason W, et al: Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: Mature progression-free survival and preliminary overall survival results in AVAglio. Neuro-Oncol 14(suppl):Abstract OT-03, 2012.
