H3K27M-mutant diffuse midline glioma pharmacotherapy: Clinical evidence and practice implications of dordaviprone

Objective: To evaluate current pharmacotherapeutic strategies for H3 K27M-mutant diffuse midline glioma (DMG), with emphasis on the clinical evidence for dordaviprone, its place in therapy, and its implications for oncology practice. Study Selection and Data Extraction: A structured literature search was conducted using PubMed and ClinicalTrials.gov through November 1, 2025. The search terms “(ONC201 OR dordaviprone) AND (‘diffuse midline glioma’ OR DMG OR H3 K27 M OR H3K27-altered)” were applied using Boolean operators. Clinical trials, cohort studies, case reports, and relevant preclinical studies evaluating pharmacologic therapies in H3 K27 M DMG were included, with emphasis on clinical outcomes and safety. The review was informed by PRISMA principles and conducted as a narrative review given the limited evidence base. A full systematic review was not possible given the limited and heterogeneous evidence base. Results: Dordaviprone received accelerated FDA approval based on the results of an integrative analysis of five phase 1 and 2 trials. The primary endpoint of overall response rate (ORR) was 20%, disease control rate 40%, and median duration of response (DOR) was 11.2 months. Fatigue, headache, vomiting, and nausea are the most common adverse effects. Discussion: Dordaviprone is the only FDA approved medication for H3 K27 M DMG. It demonstrates long-lasting radiographic and symptomatic improvement. It is currently approved for recurrence following prior therapy, not as a substitute for radiation or surgery. The ACTION trial may provide guidance on its broader use in newly diagnosed H3 K27 M DMG. Pharmacists play a role in optimizing treatment, monitoring safety and drug interactions, and supporting patient adherence. Conclusion: Dordaviprone is a novel treatment option with modest response rates and durable benefit in recurrent/progressive H3 K27 M DMG. Ongoing trials may further define its role in earlier lines of therapy.