Bridget M. Kuehn

Results from a genomic and molecular analysis presented at the ASCO Annual Meeting on June 2, 2015,

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

Clinicians currently rely on histologic classifications of gliomas to help predict a patient&rsquo;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, MD, 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.

&ldquo;There is a paucity of biologic and clinical trial data on low-grade gliomas,&rdquo; said Howard Alan Fine, MD, of the Weill Cornell Medical Center in New York City, who provided an independent analysis of Weller&rsquo;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.

&ldquo;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,&rdquo; Weller said.

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.

&ldquo;It didn&rsquo;t add a lot,&rdquo; he said.

Weller predicted a new classification system is on the horizon.

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

mutations at the top of the world,&rdquo; he said.

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.

&ldquo;What we [have] today is a better understanding of the genetic and molecular biology of the disease,&rdquo; he said. &ldquo;Genotyping each individual patient is going to be critical to targeted therapy.&rdquo;

According to Fine, the Weller&rsquo;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

Articles

Results from a genomic and molecular analysis presented at the 2015 ASCO Annual Meeting and published in Acta Neuropathology indicate that 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 bevacizumab in patients with recurrent glioblastoma after progression of the disease does not improve patient outcomes, according to results from the phase II CABARET trial.

The results were presented by Elizabeth J. Hovey, MB, BS, of the Prince of Wales Hospital in Sydney, Australia, at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 2, 2015.

Bevacizumab 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.

&ldquo;We are only beginning to understand more about bevacizumab in recurrence,&rdquo; said Timothy F. Cloughesy, MD, director of the Neuro-Oncology Program at the University of California-Los Angeles Medical Center, who presented an independent assessment of Hovey&rsquo;s results.

Despite the uncertainties and a lack of high-level data, Hovey said that offering bevacizumab 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 bevacizumab 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 bevacizumab at recurrence and progression by answering two questions: whether or not adding carboplatin to bevacizumab benefited patients with a recurrence and whether or not patients benefited from continuing bevacizumab 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 bevacizumab or bevacizumab 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 bevacizumab alone at 6 months. Final results of part 1 are in press, Hovey said.

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

showed no PFS, OS, or radiologic benefit to continuing bevacizumab after progression. The median PFS in the bevacizumab group was 1.8 months compared with 2.0 months in the cease bevacizumab group (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.59-1.96;

= .81). Median OS was 3.4 months versus 3.0 months (HR = 0.84; 95% CI, 0.47-1.50;

= .56). 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 bevacizumab and those who did not, Hovey said. However, there were slightly higher rates of adverse events in the bevacizumab arm.

&ldquo;There were minimally high rates of toxicity in the bevacizumab arm,&rdquo; she said.

Hovey said the CABARET part 2 results must be put into the context of the overall evidence, some of which has been conflicting. &ldquo;But this particular study does not support the routine continuation of bevacizumab on disease progression,&rdquo; she concluded.

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

&ldquo;The data are really compelling,&rdquo; he said.

1. 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.

2. 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.

Bevacizumab After Recurrence in Glioblastoma Shows No Benefit 

Adding the immunotherapeutic vaccine rindopepimut to bevacizumab may help boost survival in patients with a genetic subtype of glioblastoma associated with poor outcomes, according to results from the phase II ReACT study presented at the American Society of Clinical Oncology Annual Meeting, May 31 2015.

mutation have more aggressive tumors that are resistant to chemotherapy, explained Fabio M. Iwamoto, MD, of Columbia University Medical Center, at an ASCO Clinical Science Symposium. This mutation is present in about 30% of glioblastomas and is estimated to contribute to about 4000 US cases and 800 EU cases of glioblastomas each year. The good news is that the mutation is very tumor specific.

&ldquo;It&rsquo;s not expressed in normal tissue, which makes it a good target for immunotherapy,&rdquo; Iwamoto said.

Rindopepimut 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 II trials in patients newly diagnosed with glioblastoma, explained David A. Reardon,MD,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 rindopepimut with anti-VEGF therapy like bevacizumab, according to Reardon, who explained that VEGF can promote immunosuppression in the tumor, so blocking immunosuppression while administering rindopepimut could further boost the immune response to the tumor.

The phase II ReACT trial put this theory to the test and demonstrated an OS benefit for patients with relapsed glioblastoma who were treated with rindopepimut in addition to bevacizumab. In the trial, 72 patients with glioblastoma who were bevacizumab na&iuml;ve and

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

Both Reardon and Iwamoto, who gave an independent assessment of the study, agreed that the study confirmed that rindopepimut 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 bevacizumab or signs of cerebral edema, he noted.

&ldquo;Rindopepimut 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,&rdquo; Reardon said.

In the intent-to-treat analysis at 6 months, PFS in the bevacizumab/placebo vaccine control group was 16% compared with 28% in the bevacizumab/rindopepimut group, Reardon reported. The Kaplan Meyer curves of the data showed that for much of the first 6 months the two groups had very similar PFS, but at the end of the 6-month period the rindopepimut 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&rsquo; tumors and found an improved response in the rindopepimut group compared with the control (30% vs 18%). Reardon said patients in the rindopepimut 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, &ldquo;It&rsquo;s hard to define progress by imaging.&rdquo;

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

&ldquo;Our patients will be very happy to know that rindopepimut is associated with a reduction in corticosteroid usage,&rdquo; Reardon said. &ldquo;A higher percentage were able to come off of corticosteroids and maintain being off for a prolonged period.&rdquo;

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 rindopepimut arm (a 43% reduction in the hazard ratio). These benefits were maintained even within patient subgroups.

&ldquo;When we looked at outcome across a variety of prognostic factors, the addition of rindopepimut improved [OS] across groups,&rdquo; Reardon said. 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 4-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,&rdquo; Reardon said. 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.&nbsp;&ldquo;The overall survival is clearly different,&rdquo; Iwamoto said.

Data from a phase III randomized trial of rindopepimut in newly diagnosed patients with glioblastoma are expected in the next 2 months, Reardon noted.

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

Immunotherapy Combo Extends Survival for Patients With Relapsed Glioblastoma 

-mutant late-stage melanoma derive a lasting overall survival (OS) benefit from treatment with the combination of dabrafenib and trametinib compared with dabrafenib and placebo, according to the final results from the COMBI-d phase III double-blinded trial, which were presented at the American Society of Clinical Oncology Annual Meeting on May 31, 2015

Treatment with BRAF-inhibitors such as dabrafenib has been shown to increase progression-free survival (PFS) in patients with advanced melanoma who have

mutations, stated Georgina V. Long, BSc PhD MBBS FRACP, an associate professor of melanoma biology and translational research at the University of Sydney in Australia. However, there is a downside to this genetically targeted therapy. &ldquo;It causes hyperproliferative skin toxicity, including cutaneous squamous cell carcinoma and hyperkeratotic lesions due to paradoxical activation of the MAP kinase pathway,&rdquo; Long said.

Long noted that adding an MEK inhibitor counteracted this adverse effect in preclinical studies and helped delay the emergence of drug resistance. These findings led to the launch of 3 phase III clinical trials of a BRAF-inhibitor paired with a MEK inhibitor, including COMBI-d, its sister study COMBI-v, and CoBRIM, a trial comparing MEK-inhibitor cobimetinib and BRAF-inhibitor vemurafenib with cobimetinib alone. All three studies found a decrease in skin toxicity with the combination of a BRAF inhibitor and a MEK inhibitor. The COMBI-d trial is the first of the three studies to report final results.

) enrolled 423 treatment-na&iuml;ve adults with stage 3C or stage 4 melanoma expressing a

mutation. Only those patients whose tumors could not be surgically removed were included in the study. Half of the enrolled patients (n=211) were randomized to receive dabrafenib and trametinib, while the other half were randomized to receive dabrafenib plus a placebo (n=212).

Preliminary results of the trial published in November 2014 demonstrated that the combination of dabrafenib and trametinib increased PFS.

Patients in the combination group had a median PFS of 9.3 months, compared with 8.8 months in the patients receiving dabrafenib and placebo (HR 0.75; 95% CI, 0.57-0.99,

= .03). Overall, two-thirds of the patients in the combination group responded compared with half of the patients taking dabrafenib and placebo.

Patients in the combination treatment group were also less likely to develop cutaneous squamous cell carcinomas compared with the patients taking dabrafenib and placebo (2% vs 9%); however, more patients in the combination group experienced pyrexia (51% vs 28%), according to the published results.

The final results showed an OS advantage for the combination treatment. The median OS was 25.1 months (95% CI 19.2-not reached) in the combination treatment arm compared with 18.7 months (CI 15.2-23.7) in the dabrafenib plus placebo arm. Three-quarters (74%) of patients in the combination arm were alive at year 1 and 51% were alive at year 2, compared with 68% and 42%, respectively, of patients in the dabrafenib/placebo arm.

In the final analysis, median PFS was 11 months for dabrafenib plus trametinib versus 8.8 months for dabrafenib plus placebo (HR 0.67, 95% CI 0.53-0.84;

= .0004; unadjusted). Toxicities were manageable and no new or unexpected adverse events have been identified during the additional 17 months of follow-up since the primary results, Long said.

&ldquo;Dabrafenib combined with trametinib represents a new targeted therapy standard of care for

mutation-positive primary metastatic melanoma,&rdquo; Long concluded.

Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, Texas, noted that the COMBI-d study was very well conducted. These new data make it time to take a closer look at whether there is a meaningful difference in the long-term PFS of patients taking dabrafenib with trametinib compared with dabrafenib alone, he said.

Kopetz added that he was impressed by the OS results. He noted that the post-progression therapy received by patients in the trial would have actually favored the dabrafenib plus placebo arm, which suggests that the results are robust despite a potential confounder. Of the 30% of patients in the trial who continued past progression, half of those who were in the dabrafenib plus placebo arm received other therapies, compared with only about one-third of those in the combination arm, Long

&ldquo;I&rsquo;d say it is a very important, meaningful improvement in overall survival,&rdquo; Kopetz said.

1. Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF

mutation-positive cutaneous melanoma. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 102.

2. Long GV, Stroyakovsky D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial [published online May 31 2015].

. 2015.  doi.org/10.1016/S0140-6736(15)60898-4.

3. Long GV, Stroyakovsky D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.

Patients with BRAF-mutant late-stage melanoma derive a lasting overall survival (OS) benefit from treatment with the combination of dabrafenib and trametinib compared with dabrafenib and placebo, according to the final results from the COMBI-d phase III double-blinded trial.

Bridget M. Kuehn | Authors

Articles

Genomic Profiling Provides Much-Needed Prognostic Data in Glioma

Bevacizumab After Recurrence in Glioblastoma Shows No Benefit

Immunotherapy Combo Extends Survival for Patients With Relapsed Glioblastoma

BRAF/MEK Combo Shows Overall Survival Benefit at 2 Years in Melanoma Patients