Bridget M. Kuehn

Low-grade gliomas may be classified into three distinct prognostic categories based on genomic data. This conclusion came from a genomic and molecular analysis presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago on June 2, 2015,

Clinicians currently rely on histologic classifications of gliomas to help predict a patient’s prognosis and to select treatment, but for gliomas that the World Health Organization (WHO) classifies as grade II or III — astrocytic, oligodendroglial, and oligoastrocytic glioma &mdash; histologic information may not be enough, according to Michael Weller, chair of the Department of Neurology at the University Hospital Zurich, Switzerland, and his colleagues.

 Classifications in these groups by histology alone are not always consistent among clinicians, especially for oligoastrocytomas. The clinical outcomes vary greatly with the grades, and there is little standardization of treatment options for each grade.

“There is a paucity of biologic and clinical trial data on low-grade gliomas,” said Howard Alan Fine, of the Weill Cornell Medical Center in New York City, who provided an independent analysis of Weller’s presentation. This has made it difficult for clinicians to counsel patients and select treatment options.

To overcome the limitations of the current classification system, clinicians and clinical investigators are increasingly turning to molecular markers such as the expression of certain mutations or genomic patterns. They hope that more accurate classifications would provide more accurate prognostic information, help guide treatment choices, and lead to improved clinical trials.

“There is increasing use of molecular markers for diagnostic purposes, although there is a lot of knowledge and we are not [all] using it the same way,” Weller says.

 demonstrates how adding molecular markers, such as copy number variations and messenger RNA (mRNA) expression profiles, to histologic analyses might improve classification of this hard-to-classify group of tumors.

The study analyzed WHO grade II or III cerebral gliomas from 137 patients who agreed to participate in the German Glioma Network study. Weller et al used microarrays to create genomic profiles of the tumors that were then matched to histologic information and patient data. Weller explained that comparing genomic hybridization patterns among tumors allows researchers or clinicians to see patterns that they would not see by looking at individual genetic variations.

The analyses showed that there are five distinct groups based on genomic profiles: three express mutations in the 

 gene. By linking the genomic and clinical data, Weller defined three main prognostic groups. The best prognosis was associated with tumors that had both an 

mutation and 1p/19q deletions. Weller said these tumors represent a distinct disease entity.

wild-type tumors that had genomic characteristics similar to glioblastomas, such as an extra chromosome arm 7q, a missing chromosome arm 10q, a mutation in the 

 promoter gene, or amplified oncogenes. Weller argued that these may actually be unrecognized glioblastomas, which Fine agreed was a possibility.

Patients had moderate prognoses whose tumors expressed an 

wild-type gliomas without chromosome arm 7q and 10q copy variations or genotype and 

The researchers also looked at gene expression patterns in the tumors. Gene expression data suggested eight different groups, but these did not overlap well with the genome-defined groups. Weller said it was disappointing that the gene expression data were not very useful.

Weller predicts a new classification system is on the horizon.

“We are probably moving to a new classification system in the next few years where we place 

 mutations at the top of the world,” he says.

Fine agreed that the molecular low-grade glioma typing data from Weller and other trials presented at ASCO would likely lead to a new classification system for gliomas in the near future and will have a lasting impact on the treatment of gliomas.

“What we [have] today is a better understanding of the genetic and molecular biology of the disease,” he says. “Genotyping each individual patient is going to be critical to targeted therapy.”

According to Fine, the Weller’s data also provide valuable prognostic information for patients with low-grade gliomas, showing that prolonged survival is possible in two of the three genomic groups, but unlikely in the third.

1. Weller M. Molecular classification of diffuse cerebral gliomas using genome- and transcriptome-wide profiling. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 2007.

2. Weller M, Weber RG, Willsher E, et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

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Low-grade gliomas may be classified into three distinct prognostic categories based on genomic data.

Genomic Profiling Provides Much-Needed Prognostic Data in Glioma

Continuing Avastin (bevacizumab) in patients with recurrent glioblastoma after progression of the disease does not improve patient outcomes, according to results from the phase 2 CABARET trial.

 The results were presented by Elizabeth J. Hovey, from the Prince of Wales Hospital in Sydney, Australia, during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Avastin has become the standard of care for patients with new cases of glioblastoma based on promising clinical trial results, according to Hovey. But in 2009 when the CABARET trial was launched, there were few data to guide treatment decisions after recurrence or during progression.

“We are only beginning to understand more about [Avastin] in recurrence,” says Timothy F. Cloughesy, director of the Neuro-Oncology Program at the University of California-Los Angeles Medical Center, who presented an independent assessment of Hovey’s results.

Despite the uncertainties and a lack of high-level data, Hovey says that offering Avastin after a patient has progressed on the drug has become common among oncologists. She explained that clinicians fear a rapid neurologic deterioration or flare-up after discontinuing Avastin in these patients, so they continue the therapy.

The independent investigator-initiated CABARET trial was designed to help fill in the lack of data about Avastin at recurrence and progression by answering two questions: whether or not adding carboplatin to Avastin benefited patients with a recurrence and whether or not patients benefited from continuing Avastin after progression.

) enrolled 120 patients who had a first recurrence of glioblastoma after treatment with surgery, radiotherapy, or temozolomide. In part 1 of the study, patients were randomized to receive carboplatin plus Avastin or Avastin alone. The part 1 results,

 which were presented at ASCO in 2013, found no progression-free survival (PFS) or overall survival (OS) benefit to the combination therapy compared with Avastin alone at six months. Final results of part 1 are in press, Hovey says.

In part 2 of the study, 48 patients with progression were randomized to continue or cease Avastin. The patients who continued to part 2 were on average younger and more had a grade 2 tumor, Hovey says. More than 80 percent were also taking steroids.

 showed no PFS, OS, or radiologic benefit to continuing Avastin after progression. The median PFS in the Avastin group was 1.8 months compared with 2.0 months in the cease Avastin group. Median OS was 3.4 months versus 3.0 months. Hovey noted that given the statistical power of the study it would only be able to detect large differences between the two groups, so smaller benefits could have been missed.

Preliminary analyses of the data found no significant differences in steroid use, radiologic recurrence, or quality of life between the patients who continued Avastin and those who did not, Hovey says. However, there were slightly higher rates of adverse events in the Avastin arm.

“There were minimally high rates of toxicity in the [Avastin] arm,” she says.

Hovey says the CABARET part 2 results must be put into the context of the overall evidence, some of which has been conflicting. “But this particular study does not support the routine continuation of [Avastin] on disease progression,” she concluded.

Cloughesy applauded Hovey and her colleagues for forthrightly trying to provide an answer to the question of whether or not continued Avastin after progression was beneficial. He says her data should finally debunk the idea that flare-ups routinely occur after Avastin discontinuation in patients whose disease has progressed.

“The data are really compelling,” he says.

Hovey EJ. Continuing or ceasing bevacizumab at disease progression: Results from the CABARET study, a prospective randomized phase II trial in patients with recurrent glioblastoma. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 2003.

Field KM. A randomized phase II study of carboplatin and bevacizumab in recurrent glioblastoma multiforme (CABARET). Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract 2017.

Avastin After Recurrence in Glioblastoma Shows No Benefit

Adding the immunotherapeutic vaccine Rintega (rindopepimut) to Avastin (bevacizumab) may help boost survival in patients with a genetic subtype of glioblastoma associated with poor outcomes, according to results from the phase 2 ReACT study.

These results were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

mutation have more aggressive tumors that are resistant to chemotherapy, explained Fabio M. Iwamoto, the deputy director of the Division of Neuro-oncology at Columbia University Medical Center. This mutation is present in about 30 percent of glioblastomas and is estimated to contribute to about 4,000 U.S. cases and 800 EU cases of glioblastomas each year. The good news is that the mutation is very tumor specific.

“It’s not expressed in normal tissue, which makes it a good target for immunotherapy,” Iwamoto says.

Rintega targets cells that carry the mutation for destruction by the immune system, and the drug has demonstrated improved progression-free survival (PFS), overall survival (OS), and a good safety profile in three phase 2 trials in patients newly diagnosed with glioblastoma, explained David A. Reardon, clinical director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, who presented the ReACT results. The vaccine has also been used on a compassionate basis in patients with relapsed glioblastoma, according to Reardon.

There is also a strong case for combining Rintega with anti-VEGF therapy like Avastin, according to Reardon, who explained that VEGF can promote immunosuppression in the tumor, so blocking immunosuppression while administering Rintega could further boost the immune response to the tumor.

The phase 2 ReACT trial put this theory to the test and demonstrated an OS benefit for patients with relapsed glioblastoma who were treated with Rintega in addition to Avastin. In the trial, 72 patients with glioblastoma who were Avastin naïve and 

positive experiencing their first or second relapse were randomized to receive Avastin plus an injection of Rintega or Avastin plus a placebo injection.

Both Reardon and Iwamoto, who gave an independent assessment of the study, agreed that the study confirmed that Rintega has a good safety profile in this patient population. Reardon said that the vaccine was only associated with mild and temporary injection-site reactions. There were no unexpected toxicities associated with Avastin or signs of cerebral edema, he noted.

“[Rintega] has had a well-established, outstanding safety profile in studies in newly diagnosed glioblastoma patients and that experience was maintained in the context of recurring patients,” Reardon says.

In the intent-to-treat analysis at six months, PFS in the Avastin/placebo vaccine control group was 16 percent compared with 28 percent in the Avastin/Rintega group, Reardon reported. The Kaplan Meyer curves of the data showed that for much of the first six months the two groups had very similar PFS, but at the end of the six-month period the Rintega group began to show response. This finding will have important implications for the design of future studies, according to Iwamoto, who noted that the studies should be designed so they can be extended, if necessary, to give patients enough time to respond.

An independent panel of neuroradiologists analyzed images of the patients’ tumors and found an improved response in the Rintega group compared with the control (30 versus 18 percent). Reardon said patients in the Rintega group maintained this response longer than those in the control group, and some continue to maintain this improvement. Iwamoto cautioned that evidence from studies of immunotherapies for solid tumors has demonstrated that, “It’s hard to define progress by imaging.”

There were also more tangible benefits for the patients administered Rintega, with 56 percent of the patients receiving the vaccine able to stop using corticosteroids compared with 42 percent of controls.

“Our patients will be very happy to know that [Rintega] is associated with a reduction in corticosteroid usage,” Reardon says. “A higher percentage were able to come off of corticosteroids and maintain being off for a prolonged period.”

Finally, the intent-to-treat analysis found that OS improved from 9.3 months in the control group arm to 11.6 months in the Rintega arm. These benefits were maintained even within patient subgroups.

“When we looked at outcome across a variety of prognostic factors, the addition of Rintega improved [OS] across groups,” Reardon says. Additionally, Reardon said that he was pleased that the patients developed a robust tumor-specific response despite their history or relapse. He noted that the study documented a four-fold increase in anti-EGFR antibody titers.

"What I've just told you is historic data; this is the first immunotherapeutic that has shown a survival benefit for glioblastoma,” Reardon says. Iwamoto cautioned that the study has a small sample size and wide confidence intervals. But he acknowledged that results of the three trials so far have been consistent. “The overall survival is clearly different,” Iwamoto says.

Data from a phase 3 randomized trial of Rintega in newly diagnosed patients with glioblastoma are expected in the next two months, Reardon noted.

Reardon DA. ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 2009.

Adding the immunotherapeutic vaccine Rintega (rindopepimut) to Avastin (bevacizumab) may help boost survival in patients with a genetic subtype of glioblastoma associated with poor outcomes.

Bridget M. Kuehn

Genomic Profiling Provides Much-Needed Prognostic Data in Glioma

Avastin After Recurrence in Glioblastoma Shows No Benefit

Immunotherapy Combination Extends Survival for Patients With Relapsed Glioblastoma

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