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

Abstract

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.