Investigational Targeted Therapies Broaden Glioma Research Efforts and Define Disease Subsets

Ashley Sumrall, MD, FACP

Although biomarker testing is a relatively new addition to the field of brain tumor research and treatment, it is imperative that glioma experts continue to integrate this approach into daily practice as actionable mutations and targeted therapies enter the glioma scene, according to Ashley Sumrall, MD, FACP.

“If we don’t go fishing for these mutations, we won’t find them. If we don’t have people sending tumors out and looking for H3K27M mutations, that limits all our progress, both in research and in helping patients,” Sumrall said in an interview with OncLive®.

In the interview, Sumrall discussed the range of unmet treatment needs for patients with gliomas, the impacts that disease classification evolutions have had on glioma diagnosis and management, and ongoing research with the DRD2 dopamine receptor–targeted agent ONC201 in patients with H3K27M-mutated disease.

Sumrall is the section chief of Neuro-Oncology and a clinical assistant professor of medicine with Atrium Health Levine Cancer Institute, as well as a faculty member for the Internal Medicine residency program and the Medical Oncology fellowship program at the Atrium Health Carolinas Medical Center in Charlotte, North Carolina. She is also a clinical assistant professor of medicine in affiliation with the University of North Carolina Chapel Hill in Charlotte.

OncLive: How are glioma treatments currently administered, and what are some of the unmet needs for patients with this disease?

Sumrall: We have been caring for patients with glioma, in particular glioblastoma, in the same manner since approximately 2005. When you compare that with the changes and developments that have occurred for other tumor types, even for brain metastases, it can be disappointing. We’ve had some small developments over the years, and yet, we’ve not made much headway.

There are so many unmet needs. When we think about approaching a patient with a new brain tumor, for example, we don’t have a way to detect this disease early or screen for this disease. Additionally, many of our patients can’t have a large surgery; perhaps they can only have a biopsy, so there are also unmet needs in the surgical space. For patients who are receiving radiation, we are constantly seeing attempts to improve delivery of radiation. Lastly, [regarding] systemic therapies, we have been using the same oral chemotherapy since 2005. We are desperate for more drugs. How will those drugs work? We continue to look for new therapies. [Will those be] new compounds? [Will they be] personalized treatments [or a novel] delivery of medication? The brain has a unique challenge in that we have the blood-brain barrier. Medications need to be able to get [into the brain], work effectively, and not cause additional neurotoxicity. There’s room for everyone at the table. There are so many unmet needs.

How do disease recurrence rates factor into treatment decisions for patients with glioma?

It depends on whether we’re talking about glioma in general or high-grade gliomas. Most people are familiar with high-grade gliomas, including glioblastoma. One [change in the field] that has changed [our practice was the] updated WHO classification in 2021. We are using biomarkers more than ever to guide our treatment. [One challenge] we’ve discovered with [using biomarkers] is that it’s taking longer to get our final pathology results back. Many of our patients will initiate chemotherapy and radiation while they’re still waiting for biomarkers to result. That has been a change for us. Some of our clinical trials are now geared to use targeted agents, either [for patients with] newly diagnosed [disease] or those who have recurrence.

[Recurrence rates] for patients with high-grade gliomas [differ depending on the source]. Much of our data in this field is more than 10 years old. As we classify our tumors, we had a [WHO] reclassification in 2016, and then again in 2021. What we call a glioblastoma today may be different than what we called a glioblastoma 10 years ago. I find [glioma management] even more challenging now and over the past 2 years vs in the earlier part of my career because I don’t want to quote an invalid or incorrect rate of recurrence to a patient. That said, most patients with grade IV astrocytoma will experience recurrence at some point. Any neuro-oncologist has a group of long-term survivors, but for the average patient, we will still often tell people that it’s unusual to go approximately 2 years without having a recurrence of high-grade glioma.

Which targeted agents for glioma, both in the frontline and recurrent settings, are you interested in?

Anyone in this field will continue to look for the golden ticket for their patients. What’s been difficult in [glioma] is that we as a field have been later to the game for personalized tumor therapies. Compared with lung cancer, the lung cancer community quickly jumped into biomarkers, and they were readily available. Today, [although] not everywhere, most patients with lung cancer will have a panel of all those actionable mutations or fusions. It’s been slower in our area [because] it’s difficult. [Adapting to a routine of] sampling tumors for profiling [is difficult, and there are] also cost limitations. Lastly, the brain is more difficult to deal with. It can be difficult to get tissue from the brain and have enough viable tissue for testing. Many of us have hoped for [the development of] CSF sequencing to be further along than it is, but that’s still a challenging area.

Before we decide which targets or drugs we’re thrilled about, we have to reflect and realize that we still don’t know the percentage of incidence for all these different mutations and fusions in our patient population. For that reason, as we see increased availability of personalized medicine and tumor profiling, I practice in this way and encourage my colleagues to profile tumors. The more data we can obtain to see how common these mutations are, the more we can advance the field. I have developed some experience in the past 2 years in treating patients with primary brain tumors with BRAF V600E mutations. It has been fun and exciting to watch responses there. The other [mutation] I’m interested in is NTRK fusions. I’ve seen some remarkable responses there. Some of our biggest questions are: How long do we treat these patients? Will they develop resistance? Only time will tell.

What research has been done with ONC201 in H3K27M-mutated glioma?

The story of ONC201 and H3K27M-mutated tumors is fascinating. Many glioma subtypes do not get much attention. Midline gliomas did not get much attention previously because we didn’t have any [treatments] to offer these patients aside from perhaps surgery or biopsy and radiation. We knew patients [with these mutations] didn’t live long. Much of our experience came from the pediatric world with [diffuse intrinsic pontine glioma]. When tumors were reclassified, we began to refer to H3K27M-mutated diffuse midline gliomas, which are actually H3K28M mutated.

The tumors that we commonly think of as having the H3K27M mutation are midline, [occurring in] the spinal cord, the brain stem, and the deep centers of the brain. However, [based on] medical literature and anecdotes from speaking to colleagues, people have also seen this mutation in the cerebellum, the thalamus, and other areas where perhaps it’s unexpected. The brain doesn’t always read the instruction manual. I will often tell [colleagues] that if [a patient has] a deep brain tumor or a tumor [they] think could have evolved from the midline, [they should] test for the H3K27M mutation. [You don’t want to miss this mutation] because there are some therapeutic options.

ONC201 is a fascinating compound. When we first started using it in the clinical trial setting, we weren’t even sure of the mechanism. A small team invested in this drug and followed it through. They worked hard with limited resources to try to show that ONC201 made a difference for patients with cancer. [This research] included patients with diffuse midline tumors. Oftentimes, patients with primary brain tumors are excluded from clinical trials. Patients with deep tumors that affect the brain stem or the midline [are often] terminally ill, and oftentimes, investigators or companies will exclude them [from trials] for that reason. The story around this compound is beautiful, because very sick patients were included. That applied to pediatric, adolescent young adult, and adult patients.

ONC201 was shown to help patients, and then the mechanism of action was unearthed a bit more. We now know that the compound works through a unique mechanism, targeting the dopamine receptor DRD2. ONC201 essentially activates a stress response, which leads to programmed cell death in cancer cells. The deep part of the brain seems to be enriched with those receptors, and therefore patients [with deep brain tumors] will respond well to this medicine, if they’re fortunate.

The other great aspects of this medicine are that it’s oral and well tolerated. The patients who go on these clinical trials often have many neurologic issues. It’s nice to offer a compound that’s well tolerated. Additionally, because it’s oral, oftentimes, patients don’t have to travel too much [to participate in] clinical trials [with ONC201]. When these tumors were described and associated with the H3K27M mutation, there were no FDA-approved medications [for patients in this population], but many of us would use temozolomide, because it is what we had. Some of our pediatric colleagues would use other compounds. We knew the patients didn’t live long; many of us would say 6 months or less. We also knew that some of these individuals would develop leptomeningeal disease. These tumors like to travel.

A real-world study was completed [which investigated] [overall survival (OS)] for patients who did not receive ONC201 or a clinical trial intervention. The median OS for those patients after first disease progression was estimated at 5 months. There was some variability. For the first time, we’ve been able to add to the literature some actual data other than guessing. We’ve also found that pediatric and adult patients may respond differently to radiation and to systemic therapy. In the early days, when data with ONC201 were presented, [investigators showed] that median OS improved [with this agent]. One estimated [median OS] was approximately 14 months after disease progression, which was a big finding. In data that were revealed several years ago, some patients responded exceptionally well [with ONC201], and others did not. Ultimately, we learned that patients with disease affecting the thalamus seem to respond better [with ONC201]. That’s felt to be due to the enriched presence of receptors in the thalamus. There have been some publications and presentations about that over the years as well.

The most recent information we’ve shared with the community comes from a publication in Cancer Discovery in November 2023. I was pleased to be part of the authorship of this paper. We investigated the clinical efficacy of ONC201 given to patients with H3K27M-mutated tumors and evaluated how progression-free survival and OS ranged for patients. This was a broad spectrum of patients, but consistently, patients [had better outcomes] when they were treated with this compound. There were few adverse effects when patients took this medication, and it was well tolerated in all the cohorts.

As part of the work that’s been done in patients with H3K27M-mutated tumors, we’ve evaluated historical controls in 1 cohort. We’ve also examined data from patients who’ve been treated on clinical trials. This is a rare tumor. We’re evaluating multiple age groups. Our numbers are small, due to the rarity of the condition. At time of recurrence or at initial treatment, patients treated with ONC201 initially had a significant increase in OS at approximately 22 months. The [OS in the] historical control [cohort] is approximately 1 year. Most patients with disease recurrence had received radiation therapy. Systemic therapy varied because there’s no FDA-approved medicine [for this population]. [Among the 36 patients who received] ONC201, the median OS was 9.3 months vs 8.1 months in the [approximately 100 patients from the historical control group].

As we consider the data we have available from previous clinical trials that encouraged treating patients from time of diagnosis, [with agents] including ONC201, many of the investigators felt that the longer patients could be exposed to this compound, perhaps the better they would do. In those phase 2 data, that [hypothesis] seemed to bear out as true. This was the rationale for the current ACTION trial [NCT05580562] that is available both in the US and internationally. We’re accruing to this study now. We are evaluating treating patients right after radiation with standard of care, which for us includes temozolomide, and then the inclusion of ONC201 in patients randomly assigned to that arm. In the previous ONC201 clinical trials, there was no randomization; all patients received the treatment. This phase 3 trial uses 2:1 randomization. [Patients have] a 1/3 chance of not receiving ONC201. We’ve been accruing to this study for some time now at my center, and we’re all anxious to see how this goes. Other clinical trials available in the US are using ONC201, but ACTION is the largest right now.

In addition to the data that have been presented with ONC201 as a single agent, this drug has also been tested in combination with another compound, paxalisib. In addition to receiving radiation therapy, patients are treated with these other two compounds. There have been some clinical trials with this combination in the US. There are still some clinical trials available for pediatric patients in the US using those 2 compounds in combination. We’re watching that with interest and are also curious as to how those data will influence the use of those compounds for adult patients in the future.

What are the next steps for the ACTION trial?

[ONC201] is on track as far as accrual. The frequency with which we’re enrolling patients is as expected [for this] rare tumor. Whenever I discuss treating patients with brain tumors, I feel obligated to also say, our professional burden is to learn as much as we can about our individual patients’ tumors and use that to help them but to also help the other patients who suffer with this condition.