ONC201 (dordaviprone) in Pediatric Diffuse Midline Glioma (H3K27-altered): Evidence of Benefit, Limitations, and the Path Forward

H3K27-altered DMGs are defined by mutations in histone H3 variants (commonly H3F3A or HIST1H3B/C), resulting in global hypomethylation at H3K27 and profound epigenomic dysregulation. These changes drive stem-like programs, treatment resistance, and diffuse infiltration within critical neural pathways. The brainstem localization in DIPG leads to early cranial neuropathies and long-tract signs, with rapid neurologic decline from disease progression.

ONC201 originated as an imipridone with reported activity on dopamine receptor D2/3 signaling and was subsequently recognized to activate the mitochondrial protease ClpP, thereby inducing mitochondrial dysfunction and activating the integrated stress response (ISR). Preclinical models of H3K27M-mutant DMG have shown that ClpP activation and ISR signaling can create a tumor-selective vulnerability by disrupting mitochondrial homeostasis, impairing OXPHOS, and altering downstream stress pathways. The Jackson 2024 review synthesizes these mechanistic insights and positions ClpP activation as a rational strategy in DMG, while emphasizing tumor-context-dependent effects and the need to optimize CNS penetration and dosing. Duchatel and colleagues (2021) reported in vitro and in vivo anti-tumor signals for ONC201 in H3K27M-mutant models, supporting clinical translation; they cautioned that while biological rationale is strong, definitive clinical efficacy was not established at that time.

Regulatory confirmation of the DMG population most likely to benefit has since matured. The FDA-approved label for dordaviprone (MODEYSO) specifies use in H3 K27M-mutant DMG with progressive disease in adults and children ≥1 year, reinforcing the target biology and clinical context in which efficacy has been most consistently observed in the aggregate evidence base.

Children with DIPG typically present with subacute neurologic deficits—cranial nerve palsies, ataxia, and long-tract signs. MRI classically shows a diffusely infiltrative, expansile pontine lesion with T2/FLAIR hyperintensity and variable contrast enhancement. Historically, imaging alone often sufficed to diagnose DIPG, but practice has shifted toward biopsy or resection in non-brainstem midline sites to confirm histology and enable molecular profiling (including H3K27-alteration), which is now essential for diagnosis, prognostication, and treatment eligibility.

Molecular confirmation of H3K27-alteration (e.g., H3K27M) is critical for patient selection with dordaviprone. The FDA label specifies that MODEYSO therapy should be based on documented H3 K27M mutation from tumor specimens, aligning clinical use with the drug’s evidence base and regulatory indication. This standardization also facilitates consistent enrollment criteria and outcome interpretation across studies.

Liquid biopsy approaches, particularly serial cell-free tumor DNA (cf-tDNA) tracking of the H3K27M mutant allele fraction, offer a minimally invasive means to monitor disease biology. Cantor et al. (2022) demonstrated that reductions in H3K27M cf-tDNA during ONC201 therapy correlated with clinical/radiographic stabilization, whereas rising cf-tDNA often anticipated progression. Although observational and limited by small cohorts, this work supports cf-tDNA as an adjunct for early response assessment and for distinguishing transient clinical improvements from genuine anti-tumor activity during therapy.

Upfront focal radiation remains the standard of care, providing transient improvement in neurologic function with median benefit measured in months. At progression, options include re-irradiation in selected patients for symptom palliation, clinical trials, and best supportive care. As of August 2025, dordaviprone (MODEYSO) is FDA-approved for adults and children aged ≥1 year with progressive H3 K27M-mutant DMG, with selection based on tumor-confirmed mutation and oral administration per the approved label. This regulatory milestone reflects sufficient benefit–risk for use at progression in this molecularly defined population.

Observed therapeutic benefits in real-world and early clinical series have been heterogeneous. The 2021 Duchatel report cataloged occasional radiographic or clinical stabilization among small, heavily pretreated cohorts, but did not establish robust efficacy. The international academia-driven compassionate-use program (Di Carlo et al., 2024) similarly found that a minority of patients derived symptomatic or disease stabilization benefits, while most progressed—consistent with the aggressive natural history of DMG. These patterns suggest that ONC201 can help a subset of patients, sometimes with meaningful symptomatic intervals, but it is not a curative monotherapy for the majority.

Tolerability has generally been acceptable, with common adverse events including gastrointestinal symptoms and fatigue; occasional hematologic or neurologic toxicities have been reported across early series and are reflected in the characterized safety profile under labeled use. Where feasible, integration of serial H3K27M cf-tDNA measurements (Cantor 2022) may help guide continuation versus transition strategies by providing early readouts of biological response. Mechanistically similar agents (e.g., next-generation ClpP activators such as ONC206) remain investigational, and rational combinations with epigenetic modulators, targeted agents (e.g., PI3K/mTOR), or radiotherapy are being tested to deepen and extend responses.

Post-approval, the interventional landscape remains active. Ongoing controlled trials that include ONC201 feature: (1) the randomized, double-blind ACTION Phase 3 trial evaluating dordaviprone following frontline radiotherapy in newly diagnosed H3 K27M-mutant diffuse glioma; (2) the BIOMEDE 2.0 adaptive platform Phase 3 trial comparing ONC201 to everolimus with historical control benchmarking; and (3) a multicenter Phase 2 trial testing combinations of ONC201 with panobinostat or paxalisib in DMG. Expanded access programs for ONC201 have largely wound down or shifted status following regulatory approval.

DMG/DIPG is a rare pediatric cancer, but its impact is disproportionate due to rapid progression, profound neurologic morbidity, and limited curative options. Access to molecular testing and to centers capable of managing progressive DMG with evolving therapeutics is a central equity concern.

The clinical trial landscape is dynamic yet challenging. As of August 27, 2025, a focused ClinicalTrials.gov query for ONC201/dordaviprone in DMG/H3 K27M identifies multiple ongoing randomized and non-randomized efforts, alongside several terminated studies—reflecting both the urgency of innovation and the complexity of demonstrating durable survival gains in this disease. In our snapshot, three ONC201 DMG-related studies are actively recruiting (including two Phase 3 trials) and three have terminated, with expanded access protocols transitioning post-approval. These data illustrate a maturing but still fragile pipeline in which rigorous design, biomarker integration, and patient-centered outcomes are increasingly prioritized.

Evidence synthesized in Jackson 2024 points to combination strategies to improve potency and durability—pairing ClpP activation with epigenetic modulators, optimized radiation schedules, or other targeted/immune approaches, while addressing blood–brain barrier penetration and intratumoral heterogeneity. Rational sequencing with re-irradiation and incorporation of CNS-penetrant agents with complementary mechanisms are logical next steps.

Biomarker enablement is crucial. Serial H3K27M cf-tDNA tracking can accelerate response adjudication and help terminate ineffective therapy earlier, conserving patient reserve for alternative strategies (Cantor 2022). Additional pharmacodynamic markers—mitochondrial stress signatures, ISR readouts, or imaging surrogates—could stratify responders and refine dose/schedule to maximize therapeutic index.

Prospective, controlled trials remain the gold standard to quantify survival benefit, quality of life, and neurocognitive outcomes with ONC201-based regimens. Post-approval commitments, pragmatic registries, and harmonized international protocols should prioritize: (1) combinations with strong mechanistic justification; (2) robust, standardized biomarker collection; and (3) patient-centered outcomes, including functional and caregiver-reported measures, to ensure that measured benefits translate into meaningful quality and quantity of life.