AACR 2009: MRI Measure Predicts Glioblastoma Response to VEGF-Inhibitor Therapy

Zosia Chustecka

April 30, 2009

April 30, 2009 (Denver, Colorado) — A new technique that measures vascular normalization on magnetic resonance imaging (MRI) scans can predict whether or not a patient with recurrent glioblastoma will respond to treatment with a vascular endothelial growth factor (VEGF) inhibitor after only 1 dose of the drug.

The finding comes from a phase 2 study of the investigational drug cediranib (under development by AstraZeneca); it needs to be confirmed in large phase 3 trials, say the researchers. They presented the results at a plenary session here during the American Association for Cancer Research 100th Annual Meeting.

Anti-VEGF therapy is becoming a standard in the care of glioblastoma, and some dramatic responses have been seen, Dan Duda, PhD, DMD, from Massachusetts General Hospital in Boston, told the meeting. "The problem is that only some patients respond," he said.

The dramatic responses have been seen with cediranib and with bevacizumab (Avastin, Genentech/Roche), both of which target vascular endothelial growth factor (VEGF), although cediranib is an oral drug and bevacizumab is injectable.

"These drugs show efficacy but their mechanism of action remains unclear," Dr. Duda said. "They prune and normalize tumor vasculature, but it remains unclear if this benefits patients."

Tumor blood vessels are highly abnormal, they are very dilated and leaky, he explained, and this frequently results in edema within the brain, which is controlled by steroids, and which affects morbidity and mortality, he explained.

The researchers developed a vascular normalization index (VNI), which measures on an MRI scan the extent to which the drug reduces tumor vascular permeability, dilation, and the vascular basement membrane thickness.

They used this index, together with blood biomarkers, in 33 patients with recurrent glioblastoma who took part in a phase 2 trial of cediranib, and found that patients with the highest VNI values had the longest survival. "Some lived for 2 years, whereas the average survival for these patients is about 1 year," noted lead author Rakesh Jain, PhD, also from Massachusetts General Hospital.

The index was predictive of response and survival after 1 dose of cediranib, Dr. Jain noted during a press conference.

To show this after just 1 dose "is remarkable," said the discussant of this paper, Alfred Young, MD, from the department of neuro-oncology at the University of Texas MD Anderson Cancer Center in Houston. "Even if the mechanism of action of these drugs is to reduce cerebral edema, patients who respond show an increase in survival."

Dr. Young said that further work is warranted to establish what VNI actually means, and to understand how 1 dose could have such a predictive effect.

More work is underway, Dr. Duda said. The team is now using VNI in patients taking various anti-VEGF drugs in 5 phase 3 clinical trials currently in progress at Massachusetts General Hospital.

"If this approach is validated in larger studies, we could use these tools to keep patients on therapies that their tumors respond to, and shift nonresponders to other therapies," Dr. Jain explained.

Tumors that do not respond to VEGF inhibitors could have a preponderance of other growth factors, Dr. Jain noted, such as basic fibroblast growth factor (BFGF) and stromal derived factor 1 (SDF1). He told Medscape Oncology that this has been shown in other tumor types; colorectal cancer patients not responding to bevacizumab and hepatocellular cancer patients not responding to sunitinib (Sutent, Pfizer) have shown high levels of SDF1. Drugs targeting SDF1 were originally developed for use against human immunodeficiency virus, but were unsuccessful in that case; there are now efforts to "resurrect" these products. Drugs against BFGF are in early development (phase 1 clinical trials).

Dr. Duda and Dr. Young have disclosed no relevant financial relationships. Dr. Jain reports acting as a consultant for AstraZeneca, Dyax, and Millenium; receiving honoraria from Roche and Pfizer; and serving on the scientific advisory board of Enlight and SynDevRx.

American Association for Cancer Research (AACR) 100th Annual Meeting: Abstract LB-94. Presented on April 20, 2009.