A move to a virtual platform didn’t diminish the quality of the 2020 Annual Meeting of the Society for Neuro-Oncology (SNO), the yearly gathering of the world’s foremost brain tumor researchers and clinicians. As usual, the National Brain Tumor Society was a proud platinum sponsor of this important conference and deployed our own team of experts to participate in hundreds of hours of live and on-demand presentations from Thursday, November 19 through Saturday, November 21. What we learn at the conference informs our own research funding, public policy advocacy, and patient support efforts. The insights we glean also allow us to keep our community apprised of some of the latest updates, discoveries, and trends happening in the neuro-oncology field. Below, we’ve distilled key takeaways that have the potential to shape the future of the brain tumor research and treatment landscape for years to come.
1. Clinical Trial Updates – Experimental Therapeutics
SNO’s Annual Meeting often covers the progress of some of the most encouraging ongoing clinical trials across the neuro-oncology community. These studies are evaluating investigational treatments that have the potential to be tomorrow’s new medicines for patients. Highlights from this year’s clinical trial updates include:
- Leaders of a phase I/II trial called GBM-001, which is evaluating a combination of immunotherapies known as INO-5401, INO-9012, and Libtayo (cemiplimab), reported that interim data shows a potential to improve survival in newly diagnosed glioblastoma (GBM) patients who are also receiving standard of care temozolomide and radiation therapy. Fourteen of the 20 patients (70%) on the trial with an inactive MGMT gene (“MGMT promoter methylated”) were alive 18 months after starting treatment. Sixteen of the 32 patients (50%) with an active MGMT gene (“unmethylated MGMT promoter”) — a more difficult group to treat — were alive after 18 months. Researchers leading the trial indicated that they hope to report additional data on potential survival benefits from this approach in the coming months.
- Kintara Therapeutics announced interim data from two ongoing phase II clinical trials evaluating its chemotherapy, VAL-083. One trial is studying the drug in both newly diagnosed and recurrent MGMT unmethylated GBM patients. The other is studying only newly diagnosed, MGMT unmethylated GBM patients. To date, each trial is showing early indications that this chemotherapy has favorable survival benefits compared to the historic experience of other chemotherapy treatments for these patients, who, for example, typically do not respond well to temozolomide. VAL-083 will now be evaluated for potential FDA approval in the NBTS-supported GBM AGILE adaptive trial platform.
- A phase I trial is studying a drug called DAY101 in recurrent pediatric low-grade glioma patients that have tumors with an alteration to any of a group of genes known as RAS/RAF/MEK/ERK. There is currently no established standard of care for these children. While the trial is small and the results are still from early in the process, it was reported that most of the 8 patients in the trial who specifically had alterations to their RAF gene showed early signs of responding positively to this experimental treatment.
- Interim data from a phase II trial evaluating Kazia Therapeutics’s drug paxalisib (GDC-0084) in newly diagnosed unmethylated GBM patients also showed preliminary signals of survival benefit for these difficult-to-treat patients compared to historical standards. For this patient population, paxalisib will also soon be entering GBM AGILE as a new treatment arm with the hopes of making the pivotal determination of its potential clinical benefit. During the conference, early results from a phase I trial of paxalisib in pediatric patients with diffuse midline glioma, including DIPG, were also presented, with data indicating that the drug warrants further investigation in this population, as well.
- The phase II CAPTIVE (KEYNOTE-192) trial is evaluating a combination treatment approach utilizing a virus-based immunotherapy known as DNX-2401 and the immune checkpoint inhibitor, pembrolizumab, in recurrent GBM patients. Results from the trial observed that median survival for patients on the treatment combination was 12.5 months, which compares favorably to typical survival times for GBM patients with recurrent disease. Half of the patients were alive after 12 months and 20 percent survived at least 18 months, including four who are still alive after 23 months. Clinical investigators and the sponsors of the trial indicated that they are now planning a pivotal phase III trial of DNX-2401 in this patient population. Early results warranting ongoing study were also presented from early-phase clinical trials and preclinical research for DNX-2401 in pediatric DIPG. NBTS provided funding to the initial research that ultimately led to the development of DNX-2401.
- Many presentations were related to the development of the drugs ONC201 and ONC206. ONC201 is a promising experimental drug that is in clinical trials for multiple subgroups of glioma patients, including DIPG patients with the common H3K27M mutation. At SNO 2020, we heard about promising results pooled from several ongoing clinical studies of ONC201 in pediatric and adult diffuse midline glioma patients, which position ONC201 on a path toward a pivotal, registration trial. NBTS is supporting a forthcoming trial of ONC201 in adult patients whose tumors have fewer copies of a gene called EGFR than most GBM patients, and some of the data presented at SNO also demonstrated further rationale for studying the drug in this patient population.
Many other trials, while early, offered continued cautious optimism. This includes a small phase I/IIa study examining the use of a focused ultrasound (called the SonoCloud-9 implantable ultrasound device) to open the blood-brain barrier to help get treatments into the brain and to the tumor, as well as encouraging results from a trial of the experimental drug known as MDNA55 in recurrent GBM patients.
2. Single-Cell Sequencing Technology
The tools and technologies that allow researchers to perform rapid tumor sequencing (“next-gen sequencing”) are themselves relatively new, only becoming widely available in the early 2000s. As the pace of innovation has accelerated in just the last handful of years, a new technology and technique has emerged providing researchers even more precise information about the makeup — the genetic and molecular underpinnings — of brain tumors. Known as single-cell sequencing, this approach is becoming more and more important as researchers continue to try and unravel the complexity of brain tumors — this was apparent at SNO 2020.
Unlike traditional “bulk” sequencing, and as the name would imply, single-cell analysis allows the study of the various, diverse cell populations that make up a tumor. This is particularly important in very heterogeneous tumors like high-grade gliomas where a tumor is actually made up of many different types of cells. NBTS has been interested in the use of this technology for years, and one of the first grants as part of our Oligodendroglioma Research Fund went to a study by Dr. Mario Suva that utilized single-cell sequencing to gain new insights into this tumor type. Dr. Suva was one of the presenters who discussed the technology at length as part of his keynote presentation at SNO 2020.
The use of single-cell sequencing factored into many of the major discussions and presentations during the three-day event. In Friday afternoon’s live plenary sessions, during award lectures and keynote speeches, single-cell sequencing was highlighted for its utility to identify the diversity of individual cells types that make up the “microenvironment” that surrounds tumors (and potentially influence how tumors respond to treatments) and the type of cells from the immune system that are most prevalent — and thus need to be taken most seriously with regards to future approaches to immunotherapy — around gliomas. Similarly, Saturday’s live sessions feature a keynote specifically on “The Power and Future of Single-Cell Technologies” and another on “Harnessing Big Data for Science,” by Dr. Suva, which again, leaned heavily on the capabilities of single-cell sequencing. This was followed by a special roundtable discussion dedicated to “Single-Cell Sequencing of Brain Tumors.”
The technique also factored into a tour de force keynote address from Dr. Paul Northcott of St. Jude Children’s Research Hospital on the molecular characterization of medulloblastoma. He and his colleagues have refined the subgroups of medulloblastoma, bringing the number of molecularly-defined subgroups to eight. This new classification will be reflected in the expected 2021 updates to the World Health Organization’s classification of brain tumors.
Single-cell sequencing is also at the crux of Project HOPE, an update of which was presented at SNO 2020. For more on Project HOPE, see NBTS’s recent webinar on the project, which we advocated to receive funding from the National Cancer Institute.
3. Liquid Biopsy
Liquid biopsy — using new techniques and tools to detect tumor cells less invasively by testing bodily fluids like blood or cerebrospinal fluid — has been a trending topic in cancer research for a number of years. Though it has proven to be more challenging to utilize this approach in brain tumors than in other cancers, neuro-oncology researchers have continued to work toward accurate and feasible methods to gain insight about tumors without having to perform a surgical biopsy. In fact, liquid biopsy projects have been features of both of NBTS’s recent adult and pediatric research consortiums, the Defeat GBM Research Collaborative, and the Defeat Pediatric Brain Tumors Research Collaborative.
In a show of the progress being made — and the challenges and opportunities that still exist to move brain tumor liquid biopsy approaches forward — liquid biopsy was a major theme at SNO 2020. On Thursday, during the conference’s annual “Education Day,” liquid biopsy was one of the three sessions of the day’s program. Likewise, during Saturday’s live sessions, “Liquid Biopsies in Neuro-Oncology” served as one of three roundtable discussions held, following a keynote address titled, “Liquid Biopsies in Cancer.”
During the Education Day session, Dr. Jillian Phallen from John Hopkins University gave a talk on “Advances in Molecular Biomarkers and Liquid Biopsy in Brain Cancer,” which illustrated that the methods of detecting fragments of DNA shed from tumor cells in various bodily fluids are becoming more and more sophisticated and it could be possible to see liquid biopsies become as commonplace as tumor sequencing in the next few years.
One such sophisticated method was presented by Dr. Houtan Noushmehr of Henry Ford Health System. His work, which is part of the NBTS-funded GLASS consortium, has led to the development of a liquid biopsy approach that detects “epigenetic” characteristic of tumor DNA in blood serum and uses these markers as a reliable way to distinguish glioma from non-glioma in patients. Epigenetics refers to alterations in the way genes are switched on and off within a tumor cell without changes to the actual DNA sequence. In this case, Dr. Noushmehr’s team used methylation patterns to classify cancerous vs. noncancerous cells. Importantly, Dr. Noushmehr’s approach was also able to distinguish between “pseudoprogression” (when a tumor appears to be progressing, but actually isn’t) from true tumor progression. As Dr. Noushmehr summarized: “Pseudoprogression is a frequent clinical puzzle after brain tumor treatment that can be indistinguishable from true progression through imaging. This can lead to severe consequences for patient management and treatment, such as unnecessary surgeries and/or stopping therapies that work.” If his approach (and/or any of the others in development) is validated and successfully implemented in routine clinical practice, it has the potential to more accurately detect and monitor gliomas through a simple blood test.
4. Quality of Life and Patient Care
A number of presentations at SNO 2020 have direct implications for managing the care of patients and improving their quality of life. Three such interesting studies point to potential new ways to help patients better cope with the associated symptoms of their tumor:
- Though guidelines from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology, which help set standards for patient care, both support early palliative care for glioblastoma patients, data suggest that these patients are less likely than other cancer patients to be referred to palliative care specialists — and when they are, it’s often much later in the course of their illness. This results in missed opportunities to improve symptom control and other important aspects of care. So researchers at the University of California, San Francisco ran a pilot program to embed a palliative care (PC) physician into their neuro-oncology clinic once a week and encouraged neuro-oncologists to refer GBM and other patients to see (either in the clinic, via telemedicine, or home visits) the PC physician within three months. At SNO 2020, they reported that, to date, 37 patients had been referred for PC, resulting in more than 100 visits for a combination of non-pain symptoms (94% of the patients), psychosocial needs (76% of the patients), and pain (71% of the patients), among other issues. Seventy-nine percent of these patients said they would recommend seeing the embedded PC specialists to other patients in the clinic. They listed benefits such as attention to staying healthy at home, discussions around preferences for future medical care, and help with coping as very important additions to their care that they received from the PC.
- Fatigue is a common and often debilitating symptom for brain tumor patients. Researchers from Edinburgh Centre for Neuro-Oncology in Scotland studied the feasibility of two different lifestyle coaching interventions for patients with high levels of fatigue: health coaching (eight structured coaching sessions on lifestyle behaviors) or health coaching plus “activation coaching” (adding two structured sessions on motivation). A control arm was used, made up of patients who did not receive any coaching. After 16 weeks, patients who received health coaching alone reported significantly reduced fatigue, as did the health coaching plus activation coaching group. Both interventions also were reported to improve depressive symptoms in patients, and patients in the health and activation coaching group reported improved quality of life measures. The researchers concluded that these lifestyle coaching methods are feasible for fatigued brain tumor patients and may improve several aspects of patient quality of life. As it was a small study, the researchers want to conduct further evaluation, but were encouraged by these early results.
- Researchers from Leiden University Medical Center in the Netherlands performed a retrospective analysis of glioma patients who had received either levetiracetam or valproic acid for epileptic seizures. Their results, which should be validated in a prospective setting, suggest that levetiracetam has superior efficacy compared to valproic acid, while showing a similar level of toxicity, and should potentially be considered the preferred choice to try first when managing epileptic seizures in glioma patients.
Other Notable Updates
A number of additional, intriguing studies were presented that defy easy categorization for recap purposes, but nonetheless, constitute important updates. These include:
- Researchers at Memorial Sloan Kettering Cancer Center looked at a group of 82 recurrent low-grade glioma (LGG) patients with mutations to one of their IDH genes (IDH1 or IDH2) to assess what changes may have occurred to these tumors after they return following initial treatment with standard therapies. The researchers found hypermutation (an unusually high number of mutations or changes) in 57% of patients in this group who had been treated with temozolomide. Among hypermutated tumors, 94% were transformed to higher WHO grades and these patients had shorter survival and worse clinical outcomes compared with patients whose tumors were not hypermutated at recurrence. These data may have significant implications for the management of IDH-mutant LGG (both oligodendroglioma and astrocytoma) at recurrence and for the interpretation of clinical trials in recurrent gliomas, as the hypermutated tumors appear to have very different mutational profiles and aggressive clinical behavior compared to non-hypermutated tumors.
- A University of Pennsylvania Health System pilot program implemented routine use of a special diagnostic test that analyzes tumor biopsy samples from adult glioma patients for specific types of mutations called “gene fusions” from August 2017 through December 2019. These fusions were found in 97 of the more than 200 patients tested (83 were GBM patients and 14 were lower-grade glioma patients). Importantly, doctors found 8 patients with so-called NTRK fusions. These are of special interest as FDA-approved drugs exist to treat patients whose tumors harbor NTRK fusions (as NBTS previously covered on our blog). And while much of the focus in neuro-oncology has been on pediatric glioma patients with these fusions (indeed, there was further information also presented at SNO 2020 from two clinical trials of the drug larotrectinib in these patient showing continued, encouraging results that “support testing for NTRK gene fusions in patients with primary CNS tumors”), information on testing for this fusion in adults has been less robust. Furthermore, the presenters noted that several of their patients with detectable NTRK fusions went to receive one of the approved drugs “with clinical benefit.” This information, combined with the identification, in 24 other patients, of different fusions that are potentially targetable with off-label FDA-approved treatments and/or drugs in active clinical trials, encouraged the presenters to conclude that routine clinical testing for gene fusions for adult patients with glioma may allow for the detection of “therapeutically targetable alterations in a meaningful proportion of cases,” but that, “[p]rospective trials are needed to determine whether targeting specific fusions is beneficial for adult patients with glioma.”
- A team from Brigham and Women’s Hospital/Harvard Medical School reported on a novel system they developed to classify meningioma tumors based on biological characteristics and nine molecular changes often found in these tumors. They tested their system by analyzing 684 meningioma tumors and found that their method outperformed the current WHO grading classification for meningiomas in predicting which tumors were most likely to recur. They believe their system could be scalable to other cancer centers and can potentially aid in the clinical management of these patients by more accurately identifying which patients would benefit from a more aggressive therapeutic approach.
- One of the only well-established risk factors for brain tumors, particularly meningiomas, is previous exposure to radiation therapy (e.g. treatment for a childhood or previous malignancy). How these tumors may differ from meningiomas that develop spontaneously has not been well studied. Researchers from Virginia Commonwealth University School of Medicine identified more than 1,000 proven or presumed meningiomas from their cancer center’s database, performing a review of medical charts to identify patients with radiation-induced meningiomas (RIMs) and their clinical characteristics. They were particularly interested in determining how the patients responded to additional treatment with radiation, which has been largely unknown. They identified 15 RIM patients in their database. Importantly, their analysis of the medical records of these 15 patients found that RIMs appear to be associated with a higher grade at diagnosis (grade II vs. grade I) and an increased risk of recurrence/progression compared to spontaneous meningiomas. Finally, they found that despite the presumed contributory role of prior radiation, RIMs demonstrate a significant rate of responsiveness to radiation treatment. Larger studies are needed to confirm these findings.
- Researchers from Dana-Farber and Boston Children’s Hospital performed a study to learn more about young adult (YA) patients (19-39 years old) with IDH-mutant glioma. They found that these patients form a unique population whose outcomes differ from IDH-mutant patients in other age groups. Particularly, they found that this population’s tumors behave more aggressively, with shorter times to progression and a higher rate of tumors transforming into a higher-grade glioma at recurrence. The analysis, however, also found that YA patients with IDH-mutant tumors received radiation after diagnosis less frequently and had lower rates of gross total resection of their tumors — and this may, at least in part, explain the faster time to progression in these patients. Researchers also identified MGMT methylation as a predictor of longer survival for these patients and the loss of a gene known as CDKN2A as predicting patients with shorter survival, though these biomarkers need to be validated in larger studies to potentially inform how these patients are treated in the future.
- ONC206 is a “second-generation” version of ONC201 (see above) that exhibits distinct biological effects and chemical properties that may make it able to treat even more subgroups of brain tumor patients — adults, children, and young adults. At SNO 2020, we heard about the potential future use of ONC206 in medulloblastoma and other brain tumor types in adult and pediatric patients.
NBTS will continue to follow these and numerous other studies in developments in the field, and as always, will keep the community updated on any important developments that impact care, treatment, and/or quality of life for patients and caregivers.