Benjamin M. Ellingson

High-grade gliomas including glioblastoma (GBM) have a terrible prognosis and survival has not changed appreciably in the last few decades. As a consequence of myriad failed trials, drug discovery in GBM has diminished extensively. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor A (VEGFA), is one of only 3 drugs (and a single device) approved by the FDA for the treatment of GBM. Despite dramatic early results, subsequent trials have not found that bevacizumab provides a long-term overall survival (OS) benefit in patients with recurrent, relapsed GBM. Clinical evidence suggests that some patients experienced significant, robust responses to bevacizumab and substantial improvement in survival. Thus, we hypothesized that a tool for identifying the patients who would have a response and robust survival benefit from bevacizumab prior to treatment would have high clinical, scientific, and economic impact.

The negative results of clinical trials in anti-angiogenic therapy for GBM have called into question the efficacy of such therapies. While some oncologists and scientists argue that bevacizumab does exactly what it was designed to do (i.e., reduce vascularity) regardless of outcome, others argue that the use of single-agent targeted therapies may not be a viable strategy for GBM in general. It is important to realize that most clinical trials in GBM tend to consider all patients equally, searching for a “silver bullet” therapeutic strategy that will benefit all patients. Thus, if a new drug has an extreme benefit in a subset of patients, this benefit can quite easily be masked by the lack of benefit in the population as a whole. Therefore, it is important to search for biomarkers that can identify these subsets in order to better understand the biology of the disease and provide patients with their best option for a long, meaningful life.

I believe our results identifying a diffusion MR signature that can identify patients with recurrent GBM and a significant OS benefit from bevacizumab have spurred new enthusiasm for bevacizumab use and will perhaps renew contemplation of how to best utilize this potent therapeutic in current clinical practice.

We have received a tremendous amount of feedback about this publication and subsequent studies on this topic that we have presented at a variety of meetings.

Since the publication of this research, we have begun to establish a large dataset of recurrent GBM therapeutic trials, including hundreds of patients in both Phase II and III trials, in order to further validate and establish diffusion MR as a predictive imaging biomarker for bevacizumab. Interestingly, our investigations, which have been presented in various forms at a number of scientific meetings in the past few years (e.g., American Society of Neuroradiology, American Society of Clinical Oncology, Society for Neuro-Oncology, and International Society for Magnetic Resonance in Medicine), appear to suggest the diffusion MR phenotype may be specific to anti-VEGF therapies in general, including but not limited to monoclonal antibodies like bevacizumab or tyrosine kinase inhibitors like cediranib or cabozantinib. We are currently consolidating these observations into a concise manuscript that should be submitted for peer review later this year.

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