EXTH-10. Prolonged Clinical Stability in an Adult with H3K27M-Mutant Diffuse Midline Glioma Treated with ONC201 and Adjunctive Multimodal Therapy: A Case Report

Diffuse midline glioma (DMG) with H3K27M mutation is a WHO grade 4 tumor with extremely poor prognosis and limited therapeutic options. ONC201, a selective DRD2/3 antagonist with mitochondrial effects, has shown early promise in clinical trials. We report a case of a 35-year-old woman with H3K27M-mutant DMG who experienced prolonged clinical and radiographic stability following treatment with ONC201 alongside bevacizumab, Boswellia serrata, and hyperbaric oxygen therapy. The patient initially presented in Fall 2021 with diplopia, gait instability, and nausea. In May 2022, she developed hydrocephalus requiring endoscopic third ventriculostomy. MRI-guided biopsy confirmed a diffuse midline glioma involving the pons, cerebellum, and thalamus. Molecular profiling revealed H3K27M mutation and IDH1-R132H wildtype status. She received chemoradiation (September–October 2022) followed by five cycles of temozolomide. In December 2023, she enrolled in a clinical trial of ONC201. From May to July 2024, she received four cycles of bevacizumab and a second radiation course (40 Gy in 16 fractions). She also initiated daily Boswellia and underwent hyperbaric oxygen therapy. From August to December 2024, MRI demonstrated reduced contrast enhancement and FLAIR signal abnormality, correlating with symptomatic improvement. As of early 2025—more than 30 months post-diagnosis—she remained clinically stable, continuing ONC201, bevacizumab, and supportive therapies. In April 2025, MRI showed disease progression, prompting a transition to Ribociclib. She was on Ribociclib for a month, and her repeat MR brain showed progression. Due to progression of her dysphagia and aspiration pneumonia, she unfortunately passed away after a total survival of approximately 3 years. This case highlights the potential of ONC201 in combination with anti-angiogenic and supportive strategies to achieve prolonged stability in H3K27M-mutant DMG. While anecdotal, the observed radiographic response and extended survival suggest potential synergy in multimodal approaches. Clinical trial enrollment remains essential for advancing therapeutic strategies in this aggressive tumor type.