Novel treatments, deeper understanding of glioblastoma biology lead to ‘turning point’

Glioblastoma is the most common primary brain neoplasm, accounting for approximately 15% of all intracranial tumors.

It also is the deadliest. Median survival is less than 15 months. Two-thirds of patients die within 2 years, and only 4% of patients live more than 5 years, according to the American Brain Tumor Association.

Although the NIH has allocated more money for glioblastoma than any other intracranial malignancy over the past 4 decades, outcomes have not improved considerably during that time due to several formidable challenges, including the aggressive nature of the disease and the inability of many treatments to breach the blood–brain barrier.

However, a deeper understanding of disease biology — and the potential to tailor treatments based on genomic drivers — have created a renewed sense of optimism in the neuro-oncology community.

“We have not seen the same type of survival improvements for glioblastoma that we have observed for non-brain cancers, but we have made a great deal of progress within the past decade,” Ashley L. Sumrall, MD, medical oncologist at Levine Cancer Institute at Carolinas HealthCare System and a HemOnc Today Editorial Board member, said in an interview. “We are seeing more breakthroughs than ever, and it truly is one of the most exciting times to be taking care of these patients.”

HemOnc Today spoke with neuro-oncologists and brain cancer researchers about recent research advances in their field; the promise that immunotherapy, viral oncolytic therapy and other novel therapeutic approaches may offer for patients with glioblastoma; and the clinical value of modest but statistically significant survival improvements.

‘A turning point’

An estimated three of every 100,000 American adults are diagnosed each year with glioblastoma, according to the American Association of Neurological Surgeons.

Standard therapy consists of surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide, an oral chemotherapy.

However, due to almost inevitable recurrence, researchers have intensified their efforts to learn more about the genomic drivers of glioblastoma in hopes this deeper understanding can lay the foundation for more effective treatments.

In November, researchers at University of Hawaii Cancer Center identified what they consider an essential driver of tumor cell invasion in glioblastoma.

Their study, published in Oncotarget, suggested the protein RSK2 — a kinase that regulates proliferation and adhesion, and that can promote metastasis — is amplified in many patients with glioblastoma, pushing malignant cells into surrounding healthy brain tissue.

This invasion contributes to the difficulty surgeons have removing tumors, thereby contributing to high recurrence rates and poor outcomes, researchers wrote. The development of compounds to target the RSK2 protein may improve patient outcomes, they added.

“The new discovery can potentially lead to a new class of drugs to treat not only brain cancers, but other invasive cancers, as well,” Randall F. Holcombe, MD, director of University of Hawaii Cancer Center, said in a press release.

Another study offered insights into the importance of acknowledging — and understanding — the heterogeneity of the disease.

Two large phase 3 clinical trials indicated antiangiogenic compounds — a class of chemotherapy drugs designed to block the growth of new blood vessels into tumors — were ineffective for glioblastoma.

However, a study published in December in Neuro-Oncology showed the subgroup of patients whose tumors were more highly vascularized were significantly more likely to benefit from antiangiogenic therapies, living an average of about 1 year longer than those whose tumors were less well vascularized.

“Our findings speak to the fact that the biology of glioblastoma can vary significantly among individuals,” researcher Daniel Rubin, MD, associate professor of biomedical data science, radiology and medicine at Stanford University School of Medicine, said in a press release. “This is a turning point. ... This shows that subtyping cancers like glioblastoma can have a huge impact on how we treat disease.”

A new modality

Roger Stupp, MD, professor and chairman of the department of oncology at University of Zurich in Switzerland, has investigated the potential of using tumor treatment fields via Optune (Novocure Ltd), a portable device through which insulated transducer arrays are placed directly on the skin in the region surrounding the tumor.

The novel therapy — intended for patients with newly diagnosed glioblastoma — creates an alternating electric field within the tumor that attracts and repels charged components of cells during mitosis, thus disrupting cell division.

Photo courtesy of Roger Stupp, MD.

Stupp and colleagues presented initial data from the first 315 patients treated in a randomized phase 3 trial at the Annual Scientific Meetings of the Society for Neuro-Oncology (SNO) and ASCO Annual Meetings in 2014 and 2015, interim analysis results of which were published in 2015 in JAMA.

Results showed the addition of tumor treating fields to temozolomide significantly prolonged median PFS (7.1 months vs. 4.2 months; HR = 0.69; 95% CI, 0.55-0.86) and median OS (19.4 months vs. 16.6 months; HR = 0.75; 0.59-0.95). The combination also improved 2-year OS (43% vs. 29%).

A late-breaking abstract presented at SNO in November included mature data from all 695 patients in the trial.

After a median 3 years of follow-up, results showed the addition of tumor treating fields to temozolomide extended PFS (6.7 months vs. 4 months; P < .0001) and prolonged OS (20.8 months vs. 16 months; HR = 0.65; 95% CI, 0.54-0.79).

Researchers also reported a higher 2-year survival rate among patients who used Optune (43% vs. 29%; P = .001), with no significant increase in serious adverse events compared with temozolomide alone.

In an interview with HemOnc Today, Stupp — who will join the faculty at Northwestern University in Chicago in April — called the data “quite sensational.”

“There is a benefit in survival comparable to what we saw 10 years ago with temozolomide added to standard radiation therapy,” Stupp said. “Second, we have established a new treatment modality that may have implications far beyond brain tumors and neuro-oncology, which may allow us to treat tumors with locoregional extension in an effective manner without inducing systemic toxicity.”

The premise of the device has been mocked by some. In a cover story HemOnc Today published in 2015, one clinician called the approach “scientifically dubious.”

However, during a discussion after Stupp’s presentation at ASCO, Martin J. van den Bent, MD, professor of neuro-oncology at Erasmus University in the Netherlands, noted the potential for patients assigned temozolomide alone to cross over to treatment with Optune may have clouded the device’s true survival benefit.

It is unclear whether Optune will be cost-effective, van den Bent said, noting treatment costs approximately $20,000 per month.

However, Sumrall indicated the data are encouraging.

“This was a randomized trial that was stopped early because patients were doing so well,” she said. “It was nothing short of a tipping point in our field.”

Unconventional treatments

Other unconventional treatments for glioblastoma also are under investigation.

Researchers from Preston Robert Tisch Brain Tumor Center at Duke University Medical Center are studying the use of a genetically engineered poliovirus.

The disease-causing ability of the polio is removed by replacing the poliovirus internal ribosome entry site with a rhinovirus internal ribosome entry site. The reengineered virus — which is infused into glioblastoma tumors — is designed to infect and kill tumor cells while activating the immune system.

In May, the FDA granted breakthrough status to the approach, which has conferred unprecedented outcomes in some patients.

Darell D. Bigner, MD, PhD, director of the Preston Robert Tisch Brain Tumor Center, and colleagues have observed durable responses in approximately 20% of the 47 patients treated so far. Two patients survived more than 4 years, with only minor residual scarring detected by MRI.

“We are encouraged by the results we are seeing, and by the amount of knowledge we have gained since our first patient was treated in spring 2012,” Bigner told HemOnc Today. “We are working closely with the FDA in developing new clinical trials, which will allow the combination of [the genetically engineered poliovirus] with chemotherapy and checkpoint inhibitors. We should be able to treat patients at other institutions soon, as well as start treating children with brain tumors.”

Although cost of this treatment will not be set until after FDA approval, it’s important to note patients should only require one intratumoral infusion of the virus, Bigner said.

In October, a 63-year-old woman with glioblastoma underwent a procedure in which a cold virus was injected into her brain tumor.

John D. Day, MD, neurosurgeon and chair of the department of neurosurgery at University of Arkansas for Medical Sciences, injected the tumor with an adenovirus. The virus multiplied, attacking cancer cells but leaving healthy cells alone.

After the procedure, the patient has received the anti–PD-1 therapy pembrolizumab (Keytruda, Merck) every 3 weeks. These infusions weaken the cancer cells and improve the immune response to attack the tumor. The patient has experienced no complications or unanticipated side effects.

Role of immunotherapy

Immunotherapy has transformed treatment of many cancer types, and trials have shown the approach may have potential to improve outcomes in glioblastoma.

“Just the fact that we have some phase 3 trials in glioblastoma, where for years we had a hard time getting past phase 2 trials, is an encouraging sign,” Michael Lim, MD, director of the brain tumor immunotherapy program at Johns Hopkins Kimmel Comprehensive Cancer Center, said in a blog post on the NCI website. “For the first time in a long time, there’s some real excitement.”

DCVax-L (Northwest Biotherapeutics), a dendritic cell vaccine, induced median survival of approximately 31 months in a phase 2 trial. A phase 3 trial is now underway.

The phase 2, multicenter, open-label CAPTIVE study is designed to evaluate the efficacy and safety of the oncolytic adenovirus DNX-2401 (DNAtrix Therapeutics) plus the anti–PD-1 therapy pembrolizumab in patients with glioblastoma or gliosarcoma that progressed after initial treatment.

Overall response rate at 3.5 years will serve as the primary outcome measure.

“We are trying to identify more specific targets so that we can attack the [malignant] cells while leaving the healthy cells alone,” Day, one of the researchers on the CAPTIVE trial, told HemOnc Today. “This is where we need to be heading with treatment. These are the strategies we need to be pursuing. I have a lot of optimism that breakthroughs are coming.”

Several investigations are underway to assess the safety and efficacy of nivolumab (Opdivo, Bristol-Myers Squibb).

CheckMate-143 — a randomized phase 2 trial — is designed to compare the safety and efficacy of nivolumab with bevacizumab (Avastin, Genentech) in more than 400 patients with recurrent glioblastoma. Researchers also are assessing the safety and tolerability of nivolumab alone or in combination with the anti–CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) in patients with previously treated disease.

The trial has completed accrual and results are expected early this year, according to Manmeet Ahluwalia, MD, director of the brain metastases research program at Cleveland Clinic and HemOnc Today’s neuro-oncology section editor.

Two other studies will assess nivolumab in combination with radiotherapy.

CheckMate-498 will compare nivolumab plus radiation therapy vs. temozolomide plus radiation therapy in patients with unmethylated MGMT. CheckMate-548 will compare the addition of nivolumab to temozolomide and radiation in patients with methylated or indeterminate MGMT.

A paper published in December in The New England Journal of Medicine summarized the case of a 50-year-old man with glioblastoma who received multiple infusions of chimeric antigen receptor (CAR)–engineered T cells that targeted the tumor-associated antigen interleukin-13 receptor alpha 2.

The treatment — administered over 220 days through two intracranial delivery routes — induced regression of all intracranial and spinal tumors. Researchers also observed increases in levels of cytokines and immune cells in the cerebrospinal fluid.

The clinical response lasted for more than 7 months after CAR T-cell therapy initiation, with no grade 3 or higher toxic effects.

The patient’s disease recurred at four new locations after 16 cycles of CAR T-cell therapy; however, the case report provides preliminary evidence of the antitumor activity and safety of this immunotherapy approach in patients with malignant brain tumors, researchers wrote.

Research into these types of therapeutic approaches have the potential to dramatically alter the treatment landscape.

“The more we learn, the more that we see that chemotherapy and radiation therapy are just not enough for patients with glioblastoma,” Sumrall said. “We have to broaden our ideas about other ways to treat the cancer.”

Older patients

Glioblastoma disproportionately affects older patients. The average age at diagnosis is 64 years.

However, no clear treatment guidelines for this patient population exist, and therapeutic approaches vary considerably.

James R. Perry, MD, FRCPC, chair in brain tumor research at Odette Cancer Centre at Sunnybrook Health Sciences Centre in Toronto, and colleagues conducted a global randomized trial to assess the addition of concomitant and adjuvant temozolomide to hyperfractionated radiation therapy for older patients with newly diagnosed glioblastoma.

Researchers randomly assigned 562 patients (median age, 73 years; range, 65-90) to 40 Gy radiation therapy in 15 fractions, with or without 3 weeks of concomitant temozolomide and monthly adjuvant temozolomide (n = 281 in each group). Adjuvant temozolomide continued for up to 12 cycles or until disease progression.

Results — presented in June at the ASCO Annual Meeting — showed patients assigned temozolomide achieved longer median PFS (5.3 months vs. 3.9 months; HR = 0.5; 95% CI, 0.41-0.6) and OS (9.3 months vs. 7.6 months; HR = 0.67; 95% CI, 0.56-0.8).

Patients with MGMT–methylated tumors derived the greatest benefit from temozolomide. Among this subgroup, median OS was 13.5 months among those assigned temozolomide vs. 7.7 months for those assigned radiation alone (HR = 0.53; 95% CI, 0.38-0.73).

A quality-of-life analysis showed no differences in physical, cognitive, emotional or social functioning between arms. Patients assigned temozolomide reported more nausea, vomiting and constipation than those assigned to radiation alone.

“The studies that we have in patients over 65 years have only compared radiation schedules head-to-head, or radiation alone vs. temozolomide alone,” Perry said during a press conference. “There has never been a trial of combined chemotherapy with radiation in elderly patients. Oncologists now have evidence to consider radiotherapy with temozolomide in all newly diagnosed elderly patients.”

Perry and colleagues reported high patient adherence to therapy. More than 97% completed 3 weeks of chemoradiation.

“A lot of people are excited about this trial,” Sumrall said. “Many times, patients who are elderly are excluded from trials. ... It was nice to finally see our elderly patients being treated so aggressively. Researchers did not shy away from giving chemotherapy plus an abbreviated course of radiation to these patients. Treatment was effective and well tolerated.”

Ahluwaliaand colleagues retrospectively evaluated outcomes of 567 older patients with glioblastoma treated at Cleveland Clinic between 2000 and 2015. All patients were aged 65 years or older (median age, 73 years).

Twenty-eight percent of patients underwent gross total resection, 28.8% underwent subtotal resection and 43.2% underwent biopsy. Two-thirds (64%) received chemoradiation, 34% received radiation and 2% received chemotherapy.

In the entire cohort, researchers reported median PFS of 4 months and median OS of 7.11 months.

Patients who underwent subtotal resection or biopsy demonstrated higher risk for progression and death than those who underwent gross total resection (P < .001).

Those who underwent chemoradiation achieved longer PFS (6.1 months vs. 3.2 months; HR = 0.47; 95% CI, 0.37-0.59) and OS (11.4 months vs. 5 months; HR = 0.44; 95% CI, 0.34-0.56) than those who underwent radiation alone. The OS benefit with chemoradiation was most evident among patients with MGMT–methylated tumors (17.9 months vs. 5.3 months; HR = 0.22; 95% CI, 0.07-0.65).

Although the results of this study were consistent with those reported by Perry and colleagues, Ahluwalia emphasized there was one caveat.

“Patients in our study were treated with 6 weeks of radiation vs. short-course radiation in the Perry cohort,” he said. “However, if you were to put this into perspective and cross-compare the two studies, the combination of chemotherapy plus radiation therapy appears to lead to better outcomes in elderly patients compared with radiation alone.”

Statistical significance vs. clinical meaning

Although many of the survival improvements reported in modern glioblastoma trials are modest, there are multiple reasons why gains measured in months rather than years should not be discounted, experts said.

First, any research advance can be valuable to those living with the disease.

“When we see just a little bit of progress in a trial, it can be so meaningful for patients,” Sumrall said. “For them, it may translate into seeing an important life event.”

Second, quality of life has improved along with quantity of life, Bigner said.

“When looking at patients today in comparison with patients we treated at the beginning of our respective careers, we have truly seen a positive impact,” Bigner said. “Our treatments are less toxic, and our patients are clearly experiencing better quality of life than they did years ago.”

Finally, trial data from the past few years highlight the heterogeneity of glioblastoma and illustrate the importance of identifying which patient subgroups may derive the most benefit from a given approach.

“For me, the take-home message ... is that we should individualize treatment for our patients depending on how their tumor looks under the microscope,” Sumrall said.

Even incremental improvements help demonstrate the feasibility of certain treatment approaches and provide a foundation on which future investigations can build, Stupp said.

“This has impact, as it ultimately leads to better treatment,” he said. “Better understanding of disease allows us to better target treatment. This will increase our success [and extend] the survival of our patients.” – by Jennifer Southall

Click here to read the , “Should immunotherapy be the standard of care for patients with glioblastoma?”

References:

American Brain Tumor Association. Glioblastoma. Available at: www.abta.org/brain-tumor-information/types-of-tumors/glioblastoma.html. Accessed on Dec. 27, 2016.

Brown CE, et al. N Engl J Med. 2016;10.1056/NEJMoa1610497.

Gallego O. Curr Oncol. 2015;doi:10.3747.co.22.2436.

Liu TT, et al. Neuro Oncol. 2016;doi:10.1093/neuonc/now270.

Mohapatra, S, et al. Abstract ACTR-44. Presented at: Annual Meeting of the Society for Neuro-Oncology; Nov. 17-21, 2016; Scottsdale, Ariz.

National Brain Tumor Society. Tumor types: Understanding brain tumors. Available at: braintumor.org/brain-tumor-information/understanding-brain-tumors/tumor-types. Accessed on Dec. 27, 2016.

NCI. SEER Stat Fact Sheets: Brain and other nervous system cancer. Available at: seer.cancer.gov/statfacts/html/brain.html. Accessed on Dec. 27, 2016.

Perry JR, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Stupp R, et al. Abstract LBA1. Presented at: Annual Meeting of the Society for Neuro-Oncology; Nov. 17-21, 2016; Scottsdale, Ariz.

Stupp R, et al. JAMA. 2015;doi:10.1001/jama.2015.16669.

Sulzmaier FJ, et al. Oncotarget. 2016;doi:10.18632/oncotarget.13084.

Young RM, et al. Ann Transl Med. 2015;doi:10.3978/j.issn.2305-5839.2015.05.10.

For more information:

Manmeet Ahluwalia, MD, can be reached at ahluwam@ccf.org.

Darell D. Bigner, MD, PhD, can be reached at darell.bigner@duke.edu.

John D. Day, MD, can be reached at jdday@uams.edu.

Roger Stupp, MD, can be reached at roger.stupp@usz.ch.

Ashley L. Sumrall, MD, can be reached at ashley.sumrall@carolinashealthcare.org.

Disclosure: Bigner reports equity ownership in Istari Oncology, which has licensed the genetically modified poliovirus. Stupp reports an unpaid consultant/advisory role with, as well as travel expenses and accommodations from, Novocure. Ahluwalia, Day and Sumrall report no relevant financial disclosures.