Articles Tagged: diffuse midline glioma

3 articles found

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

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is among the most devastating pediatric brain tumors. Most cases harbor the hallmark histone H3 K27-alteration (commonly H3K27M), which rewires epigenetic programs and drives aggressive, infiltrative growth in the brainstem and other midline structures. Historically, focal radiation yields temporary neurologic improvement but nearly universal relapse. Durable disease control with systemic therapy has remained elusive. ONC201 (dordaviprone), the first-in-class imipridone and a pharmacologic activator of the mitochondrial protease ClpP that triggers the integrated stress response, has been extensively explored preclinically and clinically in DMG. As of August 2025, the U.S. FDA has approved dordaviprone (brand name MODEYSO) for adults and pediatric patients aged 1 year and older with H3 K27M-mutant DMG and progressive disease, with Jazz Pharmaceuticals as the NDA holder (NDA 219876), based on safety and efficacy data in this molecularly defined population. Compassionate-use series and translational monitoring studies suggest that a subset of patients experience clinical or radiographic stabilization, often accompanied by favorable biomarker dynamics, though broad, durable remissions remain uncommon in monotherapy settings. This review synthesizes mechanistic and clinical evidence to answer a critical question from families and clinicians: do ONC201 or related ClpP-activating agents materially help children with DMG—or do they mainly add adverse effects? We integrate regulatory developments, observational and translational data, and the current clinical trial landscape to provide a balanced, evidence-based appraisal.

ONC201dordaviproneMODEYSO+17 more

Diffuse Intrinsic Pontine Glioma (DIPG) and H3K27M-Altered Diffuse Midline Glioma: Molecular Diagnostics, Therapeutic Frontiers, and Clinical Trial Landscape in 2025

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem glioma that classically arises in the pons and is characterized by diffuse infiltration, lack of surgical resectability, and historically poor outcomes. Over the last decade, molecular profiling has reframed DIPG within the broader category of diffuse midline gliomas (DMG), notably those harboring histone H3 lysine 27 to methionine mutations (H3K27M). This oncohistone change defines a biologically distinct subset strongly associated with adverse prognosis and unique epigenetic dysregulation. Clinically, the disease presents with rapidly progressive cranial neuropathies, long tract signs, and cerebellar dysfunction. Conventional focal radiotherapy remains the mainstay of initial disease control, while multimodal strategies—including re-irradiation at progression, locoregional delivery, and experimental immunotherapies—are being actively evaluated. In 2025, early-phase studies report feasibility and immune activation with oncolytic viruses, GD2-directed CAR T cells, and convection-enhanced radioimmunotherapy, reflecting a maturing translational pipeline. Importantly, in August 2025 the FDA approved oral dordaviprone (MODEYSO) for H3 K27M–mutant diffuse midline glioma with progressive disease in patients 1 year of age and older, marking a significant regulatory milestone that is reshaping trial design and clinical pathways in this population. This review synthesizes evidence across diagnostic pathology, clinical trials, and emerging therapeutics. We emphasize validated biomarkers such as H3K27M immunohistochemistry (IHC), evolving locoregional strategies (e.g., convection-enhanced delivery), and immuno-oncology approaches (oncolytic adenoviruses expressing IL-12 and GD2-directed CAR T cells). We also summarize the active clinical trials landscape using registry data to guide clinicians in current options and near-term developments.

DIPGDiffuse Midline GliomaH3K27M+27 more

Diffuse Midline Glioma in 2025: From H3 K27M–Targeted Therapeutics to Regulatory Milestones and System-Level Readiness

Diffuse midline glioma (DMG), frequently characterized by H3 K27M alterations, remains one of neuro-oncology’s most aggressive pediatric and young adult malignancies with historically limited therapeutic gains beyond radiotherapy. The clinical landscape is shifting, however, with the emergence of molecularly targeted approaches and structured regulatory progress. Notably, the FDA has granted approval to dordaviprone (Modeyso) for H3 K27M-mutant DMG with progressive disease, marking a watershed moment for this rare, lethal tumor and establishing a new standard for molecularly selected care pathways in both adults and children 1 year and older (FDA OpenFDA drug label data, effective 2025-08-08, NDA 219876). This approval aligns with a body of clinical and translational research, including integrated analyses of ONC201/dordaviprone monotherapy and systematic syntheses of pediatric DMG treatment exposures and survival correlates, as well as an expanding horizon of rational combination strategies. While CDC cancer surveillance tools do not directly track DMG as a distinct entity, the evolving trial ecosystem captured via ClinicalTrials.gov demonstrates sustained momentum. Multiple ONC201-containing studies are recruiting within DMG-focused platforms and expanded access pathways remain an access bridge for patients outside of trials. In parallel, preclinical data are refining therapeutic hypotheses—such as WEE1 inhibition paired with DNA-alkylating agents—which may inform next-generation protocols and adaptive platform designs. From a health-systems vantage point, capacity to deliver timely molecular diagnostics, precision therapeutics, and high-complexity supportive care is essential; the WHO Global Health Observatory indicates U.S. physician and nursing densities of 35.75 per 10,000 and 130.28 per 10,000 respectively (2021), underscoring both capability and the need for center-of-excellence models. This brief synthesizes clinical evidence, current surveillance context, regulatory advances, and implementation considerations, and proposes forward-looking priorities for combination trials, real-world evidence, and pharmacovigilance to optimize outcomes for patients with H3 K27-altered DMG.

Diffuse midline gliomaH3 K27MDordaviprone (ONC201+10 more