No Benefit to Bevacizumab for Newly Diagnosed Glioblastoma?

Kate Johnson

June 03, 2013

CHICAGO, Illinois — A heated debate has again developed over the use of bevacizumab (Avastin, Genentech/Roche) for the treatment of glioblastoma, this time in the front-line setting in combination with chemotherapy in newly diagnosed patients.

Results from the AVAglio study, presented during a plenary session here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®), show no clear benefit, say researchers. The addition of bevacizumab to standard chemoradiation improved progression-free survival (PFS), but this did not reach the prespecified threshold for statistical significance. It also increased adverse effects, although it showed an improvement in quality-of-life measures.

A previous trial, RTOG0825, also discussed here at the meeting, showed a similar improvement in PFS (of around 3 months), but in this study it was statistically significant. However, patients receiving bevacizumab showed an increase in symptom burden and a decrease in quality of life. Neither trial showed an improvement in overall survival.

Experts are now divided over what this means for patients.

There has been previous controversy over bevacizumab and glioblastoma concerning recurrent disease. In 2010, the same clinical trial data on the use of bevacizumab in recurrent glioblastoma were used to approve it in the United States but reject it in Europe.

The data for newly diagnosed glioblastoma have experts arguing again. Many believe that there is no clear benefit to adding bevacizumab to chemotherapy in this setting, but others disagree, and indeed 1 regulatory agency has just approved this  new indication.

Ryo Nishikawa, MD, professor and chair of neuro-oncology and neurosurgery at the Comprehensive Cancer Center, International Medical Center at Saitama Medical University in Saitama, Japan, told Medscape Medical News that regulatory authorities in Japan have recommended approval of bevacizumab for newly diagnosed glioblastoma, and final approval is expected in a couple of weeks.

"For overall survival, we see no difference. Usually, oncologists think that if there is no difference in overall survival, there is no approval. But because survival in glioblastoma is quite limited, 3 or 4 months of progression-free survival is significant for patients," he said.

"Progression-free survival is kind of an arbitrary end point...but overall survival is a solid end point. Approval should be based on a solid end point, we know that. But in glioblastoma, the situation is a bit different," Dr. Nishikawa noted.

New Study Data: Is There Any Benefit?

The new data come from a placebo-controlled randomized phase 3 study, the AVAglio trial, conducted in 637 neurologically stable patients 18 years or older with newly diagnosed glioblastoma multiforme. All patients had Karnofsky Performance Scale scores of at least 60 and a tumor tissue block larger than 1 cm³.

After surgical resection, patients were randomized to receive standard chemoradiation with temozolomide plus either placebo or bevacizumab (10 mg/kg every 2 weeks).

The researchers found no statistically significant benefit to bevacizumab therapy for the 2 primary end points of overall survival and progression-free survival. However, progression-free survival was prolonged. In addition, toxicity increased in the bevacizumab group.

"We feel that bevacizumabremains an important therapy for patients with glioblastoma, but the results of this study do not support its front-line use. Rather, it can be reserved as a later treatment," said lead author Mark R. Gilbert, MD, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, during a press briefing.

Despite the data demonstrating these limitations, study discussant Howard Fine, MD, director of the Brain Tumor Center and deputy director of the NYU Cancer Institute in New York City, said he feels strongly that bevacizumab is "the single most important therapeutic agent in glioblastoma since temozolomide, maybe even more so."

It comes down to whether "benefit" is measured in terms of overall survival, progression-free survival, or quality of life, Martin van den Bent, MD, PhD, past chair of the European Organization of Research and Treatment (EORTC) Brain Tumor Group, told Medscape Medical News. That's going to be the critical part of the discussion," he said. Dr. van den Bent is professor of neuro-oncology at the Daniel Den Hoed Cancer Center, Erasmus University, in Rotterdam, the Netherlands.

In the AVAglio study, median overall survival was similar in the bevacizumab and placebo groups (15.7 vs 16.1 months; P = .21).

A confounding feature of this study was that patients in the placebo group were allowed to cross over to bevacizumab if their disease progressed, "so there's a chance that the crossover eliminated the survival benefit," Dr. Gilbert explained.

Progression-free survival was prolonged with bevacizumab, compared with placebo (10.7 vs 7.3 months). However, "even though the P value was 0.007, it did not reach our predetermined definition of significance," he noted.

"We decided that we would weight it more toward overall survival, " he explained. Therefore, the researchers chose a P value of .05 for statistical significance and then divided it between the 2 coprimary outcomes, setting a P value of .046 for overall survival and .004 for progression-free survival — which adds up to .05.

In addition to no survival benefit with bevacizumab, toxicity was higher, he noted.

Specifically, bevacizumab was associated with more hypertension than placebo (4.8% vs 1.0%), more deep vein thrombosis/pulmonary embolism (9.9% vs 7.7%), more wound issues (2.3% vs 1.0%), more gastrointestinal perforation (1.3% vs 0.7%), more significant hemorrhage (1.3% vs 1.0%), and more neutropenia (15.1% vs 7.3%).

Secondary analyses, which evaluated the impact of MGMT methylation and a 9-gene signature on treatment outcome, failed to identify any subgroups that benefited from bevacizumab, he added.

More patients free of progression on imaging showed a decline in these functional domains, said Dr. Gilbert. "Put in the context of the prolongation of progression-free survival, that made the difference. Not only did we not hit the progression-free survival target that was prespecified, we also saw that, over time, a portion of the patients who were progression-free on bevacizumab did not maintain their overall function status."

Quality-of-life results from the AVAglio study, reported separately (abstract 2005), suggest an improvement in patients who had additional bevacizumab compared with placebo. However, this contrasts with the results for quality of life, symptom burden, and neurocognitive functions in the RTOG-0825 study, presented separately (abstracts 2003 and 2004), which show that patients in the bevacizumab group generally fared worse than those in the placebo group.

These RTOG 0825 quality-of-life results are in contrast to those from the AVAglio trial — a similarly designed study, sponsored by Roche, that evaluated the addition of bevacizumab to standard chemoradiation, said Dr. Fine. Results from AVAglio were reported in a separate study (abstract 2005).

"Strikingly Different" Results for QoL

However, the quality-of-life data from AVAglio were "strikingly different" than the RTOG data, noted Dr. Fine.

"RTOG showed worsened patient-reported symptom burden and worsening neurocognitive function with bevacizumab. By contrast, the AVAglio trial showed the exact opposite — improved quality of life, prolonged Karnofsky Performance Scale scores, and reduced doses of steroids," he added.

A possible explanation for this difference is the fact that AVAglio did not evaluate neurocognitive function, which is particularly sensitive to disease progression. Dr. Fine suggested that a decline in neurocognitive function could be masked by the ability of bevacizumabto stabilize the blood–brain barrier and decrease gadolinium enhancement on MRI scan.

Additionally, radiographic definitions of progression-free survival were different in the two trials.

But the whole issue of defining progression-free survival by radiographic parameters is a particular problem when dealing with bevacizumab, Dr. van den Bent told Medscape Medical News.

"VEGF inhibitors like bevacizumabdecrease the leakiness of the vessels, making it more difficult to detect progression, he said. "But, is what we are seeing an antitumor effect or are we simply looking at scans that look better because they have less leaky vessels?"

This is where the patient's experience during progression-free survival becomes particularly important, he noted.

"What does the increase in progression-free survival mean?" he said. "If you see an increase in progression-free survival, does that imply that the patient will live in good clinical condition longer? I think it's going to be a heated debate, where we need data and more understanding of the data before we can make any certain statements."

On the basis of the AVAglio trial, and now results from the RTOG-0825 trial, "there does not appear to be a clinical benefit from upfront treatment with bevacizumab in glioblastoma," said Christina Tsien MD, from the University of Michigan in Ann Arbor, during at a "highlights of the day" session.

She added that bevacizumab might be of benefit in particular subsets of patients, such as those who cannot undergo resection, but at the moment, there are no biomarkers that would indicate which patients would benefit.

Dr. Tsien also mentioned that the effects of bevacizumab in reducing vascular permeability and edema might lead to a "pseudo response," which looks like a response on imaging, whereas in fact the tumor is progressing. Conversely, "pseudo progression" is a possibility in the placebo group, where there is no antiangiogenic effect of bevacizumab; patients might feel worse and imaging might suggest progression, but the tumor could still be responding.

I remain doubtful about the true antitumor efficacy of bevacizumab in glioblastoma. Dr. Deepa Subramaniam

"I remain doubtful about the true antitumor efficacy of bevacizumab in glioblastoma," said Deepa Subramaniam, MD, director of the brain tumor center at the Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C. "It is certainly a very helpful drug in the symptomatic patient and does improve survival in very specific patient subsets, but I do not think we know what those subsets are, meaning we have no reliable predictive markers for benefit from bevacizumab. This is true of the role of bevacizumab in most other solid tumors for which it is approved."

Since the US Food and Drug Administration granted accelerated approval of bevacizumab for recurrent disease, there has been an increase in its off-label use for newly diagnosed disease, according to several experts at the meeting.

There is a convincing biologic explanation for why the drug would be beneficial in recurrent but not newly diagnosed disease, explained Dr. Fine.

"There are 2 predominant growth patterns within glioblastoma — angiogenic and nonangiogenic," he explained.

At the time of tumor progression, patients have angiogenic-driven tumors. "If you treat them at this time with an antiangiogenic agent, such as bevacizumab, you could see benefit." This is not likely the case with newly diagnosed disease, he said. In fact, the use of bevacizumab in newly diagnosed patients could result in a more treatment-resistant recurrence. "If they've had long-term bevacizumab from the start, then when they recur, it is a nonangiogenic recurrence," which will not respond to bevacizumab, he explained.

The research was supported by the National Cancer Institute and Genentech. Dr. Gilbert reports serving as a consultant or in an advisory role for Novartis, EMD Serono, Genentech, and Merck; receiving honoraria from Novartis, EMD Serono, Genentech, and Merck; and receiving research funding from GlaxoSmithKline, Genentech, and Merck. RTOG 0825 investigator Michael Vogelbaum, MD, PhD, reports receiving honoraria from Merck. RTOG 0825 investigator Howard Colman, MD, PhD, reports serving as a consultant or in an advisory role for Castle Biosciences and Roche/Genentech. RTOG 0825 investigator Terri Armstrong, PhD, ANP-BD, reports receiving research funding from Genentech. RTOG 0825 investigators Jeffrey Scott Wefel, PhD, and David Schiff, MD, report serving as a consultant or in an advisory role for Genentech. RTOG 0825 investigator Erik Sulman, MD, PhD, reports serving as a consultant or in an advisory role for GlaxoSmithKline, and receiving honoraria from Merck. RTOG 0825 investigator Minesh Mehta, MD, reports serving as a consultant or in an advisory role for Genentech and Merck, owning stock in Accuray, and receiving honoraria from Merck.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 1, presented June 2, 2013; Abstracts 2003, 2004, and 2005, presented June 1, 2013.



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