Dr Umemura on the Development of ONC201 in H3K27M-Mutant Diffuse Midline Glioma

Yoshie Umemura, MD, division chief, Neuro-Oncology, William R. and Joan R. Shapiro Chair for Neuro-Oncology Research, associate professor, neurology, Barrow Neurological Institute, chief medical officer, Ivy Brain Tumor Center, discusses the development of ONC201 in patients with 

Efficacy data with ONC201 in diffuse midline glioma have generated excitement, Umemura says. Early clinical observations with this agent have revealed substantial tumor volume reductions in patients with 

 mutations, Umemura notes. This mutation-specific response to the agent differentiates diffuse midline glioma from glioblastoma, a tumor type in which ONC201 has previously been shown to generate unfavorable outcomes, Umemura adds.

For instance, an integrated analysis of ONC201 monotherapy was conducted in patients with recurrent 

-mutant diffuse midline glioma. The study included 46 adult patients and 4 pediatric patients who received the agent across 4 clinical trials or 1 expanded-access protocol. This analysis demonstrated an overall response rate (ORR) per Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria of 20.0% (95% CI, 10.0%-33.7%). The median time to response was 8.3 months (range, 1.9-15.9), and the median duration of response was 11.2 months (95% CI, 3.8-not reached). Furthermore, the ORR per combined RANO-HGG/low-grade glioma criteria was 30.0% (95% CI, 17.9%-44.6%). 

These findings underscore the importance of conducting molecular diagnoses to accurately identify tumor types and tailor treatments accordingly, Umemura emphasizes. The efficacy of ONC201 in patients with 

-mutant diffuse midline glioma supports the potential use of this agent as a targeted therapy in this disease subset, Umemura explains.

Moreover, ONC201 is administered orally, which enhances its appeal for oncologists and patients, according to Umemura. The agent is also well tolerated, she notes. This ease of administration and tolerable safety profile, combined with the efficacy of this agent in a molecularly defined patient population, positions ONC201 as a promising therapeutic option for patients with diffuse midline glioma harboring 

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Yoshie Umemura, MD, discusses the development of ONC201 in patients with H3K27M-mutated diffuse midline glioma.

! I’m your host today, Caroline Seymour.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by Chimerix, we had the pleasure of speaking with Stephen Bagley, MD, MSCE, an assistant professor of medicine in hematology-oncology at the Hospital of the University of Pennsylvania, as well as section chief in Neuro-Oncology and an assistant professor of medicine in neurosurgery at Penn Medicine in Philadelphia.

In our exclusive interview, Dr Bagley discussed the evaluation of the small molecule ONC201 in the phase 3 ACTION trial (NCT05580562) in patients with 

mutant diffuse midline gliomas and explained why clinicians should consider the trial for their patients.

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Dr Bagley discusses the evaluation of the small molecule ONC201 in the phase 3 ACTION trial in H3 K27M–mutant diffuse midline gliomas.

Bagley Summarizes the ACTION trial of ONC201 in H3 K27M–Mutant Diffuse Midline Gliomas 

Following encouraging early efficacy signals seen in patients with 

-mutated diffuse midline glioma, the dopamine receptor D2 (DRD2) antagonist ONC201 (dordaviprone) is aiming to improve upon the standard of care (SOC) of radiotherapy for this subset of patients, according to Stephen Bagley, MD, MSCE. The agent is under evaluation in the currently enrolling phase 3 ACTION trial (NCT05580562).

“For patients [with] newly diagnosed diffuse midline glioma, once they complete SOC radiotherapy, there isn’t anything that’s been proven to improve outcomes. Rather than waiting for a recurrence of the tumor and then seeking out clinical trials such as chimeric antigen receptor [CAR] T-cell [therapy], the ACTION study represents an opportunity for patients to have access to an experimental therapy as part of first-line SOC. It provides access earlier in the disease course,” Bagley said in an interview with 

Currently, the SOC treatment for patients with 

-mutated gliomas is radiotherapy as no systemic therapies have proven to be effective.

 However, select centers will treat patients with temozolomide (Temodar) as adjuvant therapy with radiotherapy, but the efficacy of temozolomide in diffuse midline glioma with an 

 mutation also have high expression of 06-methylguanine DNA methyltransferase, which is known to confer resistance to temozolomide.

Notably, in a pooled analysis of patients with 

-mutated diffuse midline glioma receiving ONC201 (n = 50), 88.0% of patients received prior temozolomide which investigators noted was despite a lack of clear efficacy with the therapy in this patient population. They hypothesized administration of temozolomide was likely because it previously demonstrated efficacy combined with radiotherapy in patients with newly diagnosed glioblastoma who were not molecularly selected.

Ashley Sumrall, MD, FACP, added in an interview with 

 that the mechanism of action of ONC201 may make it an efficacious agent for patients with 

-mutated diffuse midline glioma. “ONC201 is a fascinating compound. When we first started using it in the clinical trial setting, we weren’t even sure of the mechanism [of action]. A small team [investigated] this drug and followed it through,” Sumrall said. “We now know that the compound works through a unique mechanism, targeting 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 small-molecule therapy ONC201 has specifically shown efficacy in patients with 

-mutated gliomas. In the first phase 2 study (NCT02525692) of oral ONC201 for adults with recurrent bevacizumab (Avastin)-naive glioblastoma, 1 patient enrolled who had 

-mutated thalamic glioma achieved a near complete durable response, leading investigators to turn their focus to developing the agent for patients with 

-mutated disease. Based on preclinical data and the response experienced by this 22-year-old female patient, including the complete regression of the primary thalamic lesion, investigators began to further evaluate ONC201 in patients with 

“This drug has shown significant promise in findings from earlier-phase, single-arm clinical trials in patients with diffuse midline glioma, a rare glioma that is typically more common in children but can be seen at any age,” Bagley, an assistant professor of medicine and section chief of Neuro-Oncology at the Hospital of the University of Pennsylvania and Abramson Cancer Center in Philadelphia, said. “Diffuse midline glioma affects midline structures from the spinal cord to the brainstem up to the thalamus. Historically, this has been a very difficult tumor to treat.”

Sumrall added that “the tumors we commonly think of as having the 

 mutation are midline, [occurring in] the spinal cord, the brainstem, 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 

Sumrall is the section chief of neuro-oncology and a clinical assistant professor of medicine at 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, both in Charlotte, North Carolina. She is also clinical assistant professor of medicine in affiliation with the University of North Carolina at Chapel Hill for the Charlotte campus.

Early-Phase Studies Pave the Way for ONC201

 mutation is present in diffuse midline glioma, the median overall survival (OS) has been reported to range from 11 months to 15 months. Investigators who assessed data from the phase 1 ONC014 trial (NCT03416530) and expanded access study ONC018 (NCT03134131) found that patients with nonrecurrent 

-mutated diffuse midline glioma treated with ONC201 (n = 35) experienced a median OS of 21.7 months. Median OS varied for patients treated with ONC201 in the 2 trials at 21.7 months in ONC014 (n = 24) and 13.9 months in ONC018 (n = 11), but this was not statistically different. Survival results were consistent in the 2 trials, with 30% of patients surviving for more than 24 months.

In the recurrent setting, the combined median OS in patients who received ONC201 (n = 36) was 9.3 months from recurrence and the median progression-free survival (PFS) was 3.4 months from recurrence.

-mutated disease enrolled in ONC014 had a median age of 8.2 years (range, 2-21), whereas those in ONC018 were older, with a median age of 23.7 years (range, 4-58). For patients with nonrecurrent disease, the median time from radiation to ONC201 treatment was 1.8 months (range, 0.2-15) in the ONC014 study compared with 3.8 months (range, 1-6) in the ONC018 study. These rates were 3.7 months (range, 2-18) vs 6.8 months (range, 0.5-45) for patients with recurrent disease, respectively.

A pooled study examining ONC201 also found that the overall response rate in 4 clinical trials and 1 expanded access protocol, including the ONC014 and ONC018 studies, for patients with 

-mutated diffuse midline glioma (n = 50) was 20.0% (95% CI, 10.0%-33.7%) by Response Assessment in Neuro-Oncology for high-grade gliomas criteria. One patient achieved a complete response and 20.0% of patients experienced stable disease. The disease control rate was 40.0% (95% CI, 26.4%-54.8%) and the median duration of response was 11.2 months (95% CI, 3.8-not reached).

“ONC201 showed radiographic responses in a subset of patients, and on that basis, the ACTION study was designed and is now actively recruiting patients around the world,” Bagley said. “The CAR T-cell trials at this time are still in very early days and are being tested primarily in patients with recurrent refractory tumors who have not responded to radiotherapy and other standard approaches. ONC201 is being evaluated as part of first-line management right now to try to establish a new SOC for this disease.”

Looking to the Phase 3 Setting With ACTION

The double-blind, placebo-controlled ACTION trial is randomly assigning patients 1:1:1 to receive ONC201.

 “There are 3 arms: 2 experimental arms looking at different [schedules] of ONC201 and a third arm, the placebo arm. We are actively recruiting [patients to enroll in] this trial at our site [at Penn Medicine in Philadelphia, Pennsylvania], and there are many others enrolling around the world,” Bagley said. “We anxiously await the results of this important study.”

Patients with a new histologic diagnosis of 

-mutated diffuse glioma with a weight of at least 10 kg at the time of random assignment will be enrolled in the global study. Dosing of ONC201 is based on weight, and patients with a weight of 52.5 kg or more will receive 625 mg of the agent either twice weekly or weekly. Patients with a weight less than 52.5 kg will receive a dose scaled to weight and rounded to 125-mg increments, as the agent is administered via 125-mg capsules. Those in the placebo group will receive a placebo given in the same quantity of capsules.

“Efficacy is the main question and is the primary end point for this study. This study has a dual primary end point of OS and PFS,” Bagley noted. Secondary end points encompass adverse effects (AEs) and change from baseline in clinical laboratory parameters, among others. Bagley added that there is “enough data at this point to suggest that ONC201 is not necessarily going to be hindered specifically by tumor heterogeneity, [which can be a] problem.”

Bagley explained that the inclusion of a placebo arm in addition to the rarity of the disease may serve as a potential barrier to enrollment. “This is not a common tumor, and even though there are well over 100 centers that are planning to open this study around the world, it’s still a very rare disease, and the trial is a large trial looking to enroll up to 450 patients. With such a rare disease, even with all the centers, this may take a long time to accrue. The other concern is it is a randomized, placebo-controlled trial, and oftentimes, it’s challenging to discuss the use of a placebo in a patient population where the outcomes are generally not very good. Sometimes that can hinder accrual [to trials] for difficult-to-treat cancers such as this one.”

Key exclusion criteria in the trial include having a primary spinal tumor, diffuse intrinsic pontine glioma, any concurrent malignancy, evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination, and new lesions outside the radiation field. Patients also cannot have received proton therapy for glioma or whole-brain radiotherapy.

Prior Data Show Tolerable Safety Profile With ONC201

Previous data have revealed that ONC201 is well tolerated. Notably, no dose-limiting toxicities were reported with the recommended phase 2 dose of 625 mg once weekly or twice weekly in pediatric patients with 

“The AE profile of this drug in the earlier-phase studies was very benign, well tolerated, and we don’t expect to see anything different using it in this maintenance setting after radiotherapy,” Bagley said of the ACTION trial.

In the pooled study, the most common any-grade treatment-related treatment-emergent AEs observed in patients (n = 50) included fatigue (34%), nausea (18%), decreased lymphocyte count (14%), headache (10%), and vomiting (10%). Grade 3 toxicities occurred in 20% of patients and included fatigue (10%), rash maculopapular (4%), decreased lymphocyte count (2%), and headache (2%). Twenty-three patients experienced a serious AE (46%) with the most common being hydrocephalus (8%) and nausea (8%). No treatment-related deaths occurred.

These would be incredibly significant results [if the ACTION trial findings are positive]; this would be the first systemic therapy to ever show benefit for this very difficult disease. If this is a study with positive findings, there’s reason to believe it would become a SOC and practice changing for newly diagnosed diffuse midline glioma. I can’t speak enough about the importance of this study.”

ONC201 in H3 K27M-mutant diffuse glioma following radiotherapy (the ACTION study) (ACTION). ClinicalTrials.gov. Updated February 14, 2024. Accessed February 15, 2024. 

https://classic.clinicaltrials.gov/ct2/show/NCT05580562

Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (dordaviprone) in recurrent H3 K27M-mutant diffuse midline glioma. 

. Published online February 9, 2024. doi:10.1200/JCO.23.01134

Yang Z, Sun L, Chen H, Sun C, Xia L. New progress in the treatment of diffuse midline glioma with H3K27M alteration. 

. 2024;10(2):e24877. doi:10.1016/j.heliyon.2024.e24877

Gardner SL, Tarapore RS, Allen J, et al. Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy. 

. 2022;4(1):vdac143. doi:10.1093/noajnl/vdac143

Venneti S, Kawakibi AR, Ji S, et al. Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. 

. 2023;13(11):2370-2393. doi:10.1158/2159-8290.CD-23-0131

Gardner S, Koschmann C, Tarapore R, et al. Safety of ONC201 administered two consecutive days per week in pediatric H3 K27M-mutant glioma patients.

. 2021;23(suppl 6):67. doi:10.1093/neuonc/noab196.261

Articles

The dopamine receptor D2 antagonist ONC201 is under evaluation in patients with H3K27M-mutated diffuse midline glioma in the phase 3 ACTION trial.

ONC201 Looks to Prove Efficacy in Trial For Rare H3K27M-Mutated Diffuse Midline Gliomas

Dr Bagley on the ACTION Trial of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas

Stephen Bagley, MD, MSCE, assistant professor of medicine, hematology-oncology, University of Pennsylvania Hospital, assistant professor of medicine, neurosurgery, Penn Medicine, discusses the evaluation of the small molecule ONC201 in the phase 3 ACTION trial (NCT05580562) for patients with 

Diffuse midline gliomas are rare malignancies, with a higher incidence in pediatric populations, Bagley begins. This tumor type has historically been considered difficult to treat due to its location in the central nervous system, spanning from the spinal cord to the brain stem to the thalamus, Bagley explains.

The first-in-class imipridone ONC201 (dordaviprone) penetrates the blood-brain barrier to target the dopamine receptor D2/3 (DRD2) which in turn activates an integrated stress response, thereby triggering programmed cell death in cancer cells. DRD2 is hypothesized to be enriched in these brain structures, indicating that ONC201 may have a role in the treatment armamentarium as an effective antagonist. An integrated pooled analysis of 5 open-label, early-phase trials of ONC201 has demonstrated promising efficacy signals with the agent in patients with recurrent diffuse midline glioma. Orally administered ONC201 also exhibited radiographic responses in a subset of patients with recurrent disease, Bagley notes.

Based on these initial data, the large, international, randomized ACTION trial was initiated, Bagley says. The study will enroll patients with newly diagnosed 

-mutant diffuse glioma who completed standard frontline radiotherapy. Patients will be randomly assigned 1:1:1 to receive either placebo, once-weekly ONC201, or twice-weekly ONC201 on 2 consecutive days.

The study’s primary efficacy end points are overall survival (OS) and progression-free survival (PFS), evaluated with response assessment in neuro-oncology-high grade glioma criteria by blinded independent central review. Other secondary objectives include safety, additional efficacy end points, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization.

The ongoing trial will assess the efficacy of ONC201 in a broader context and provide insight into its potential role in diffuse midline glioma, Bagley explains. As recruitment progresses, the oncology community anticipates that the results of this study will further inform the management of this challenging tumor, he says. The ACTION study is currently enrolling in the United States, with plans to open at other international sites.

Stephen Bagley, MD, MSCE, discusses the phase 3 ACTION trial evaluating ONC201 in H3K27M-mutant diffuse midline gliomas.

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 

 mutations, that limits all our progress, both in research and in helping patients,” Sumrall said in an interview with 

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 

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.

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

: 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 

 V600E mutations. It has been fun and exciting to watch responses there. The other [mutation] I’m interested in is 

 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 

-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 

-mutated diffuse midline gliomas, which are actually 

The tumors that we commonly think of as having the 

 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 

 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 

 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 

 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 

-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 

-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.

Ashley Sumrall, MD, FACP, discusses ongoing research with the DRD2 dopamine receptor–targeted agent ONC201 in patients with H3K27M-mutated glioma. 

Investigational Targeted Therapies Broaden Glioma Research Efforts and Define Disease Subsets 

Dr Sumrall on the Clinical Efficacy of ONC201 in H3K27M -Mutant Diffuse Midline Gliomas

Ashley Sumrall, MD, FACP, clinical assistant professor, medicine, University of North Carolina at Chapel Hill, medical oncologist, section chief, Neuro-Oncology, Atrium Health, Levine Cancer Institute, discusses the clinical efficacy of ONC201 in 

The investigational small molecule ONC201 functions as a dopamine receptor D2 antagonist, and has shown preclinical activity when treating gliomas and other solid tumors through dopaminergic activation integrated stress response, as well as inactivation of AKT and ERK. Patients with 

-mutant diffuse midline glioma have achieved promising outcomes when treated with ONC201, Sumrall begins. Furthermore, prior research has shown that patients with disease affecting the thalamus experience better responses with ONC201 due to an enriched presence of dopamine receptors in this structure, Sumrall notes. 

According to results from a phase 2 pilot study (NCT02525692), ONC201 treatment without molecular stratification did not improve progression-free survival compared with historical controls in patients with recurrent, bevacizumab (Avastin)–naive, IDH1/2 wild-type glioblastoma. However, the agent showed signs of anti-tumor activity in 2 of 4 patients with 

 mutations who were enrolled in the 2 glioblastoma arms of this trial. Subsequent findings from a follow-up study showed that treatment with ONC201 prolonged responses among multiple patients with 

-mutant disease in a mixed cohort of several ongoing studies (n = 18).

To further elucidate the efficacy of and mechanism underlying responses to ONC201 in this population investigators evaluated data from a completed phase 1 study (NCT03416530) and a completed expanded access study (NCT03134131), Sumrall details. Results show that patients treated with ONC201 post-initial radiation, but before recurrence, exhibited a median overall survival (OS) of 21.7 months, whereas those treated following disease recurrence had a median OS of 9.3 months. The agent was deemed well tolerated with minimal adverse effects, Sumrall adds.

The mechanistic insights from this study reveal that ONC201 disrupts integrated metabolic and epigenetic pathways, thereby addressing the pathognomonic reduction in H3K27me3. Overall, this comprehensive study supports ONC201 as a potential monotherapy for improving outcomes in 

-mutant diffuse midline glioma beyond radiation.