ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma

Area of Science:

• Neuro-oncology
• Molecular oncology
• Clinical trials

Background:

• Diffuse midline glioma (DMG) with H3 K27M mutation has a poor prognosis.
• Effective therapies for recurrent DMG are limited, with radiation therapy being the primary treatment.

Purpose of the Study:

• To evaluate the efficacy and safety of single-agent ONC201 (dordaviprone) in patients with recurrent H3 K27M-mutant DMG.
• To assess the overall response rate (ORR), duration of response (DOR), and time to response (TTR) as primary and secondary endpoints.

Main Methods:

• An integrated analysis included 50 patients with recurrent H3 K27M-mutant DMG treated with oral ONC201 monotherapy.
• Patients met Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG) and had adequate performance scores.
• Radiographic endpoints were evaluated by blinded independent central review.

Main Results:

• The ORR by RANO-HGG criteria was 20.0%, with a median DOR of 11.2 months and median TTR of 8.3 months.
• A combined RANO-HGG/LGG ORR was 30.0%.
• Significant corticosteroid dose reduction (46.7%) and performance score improvement (20.6%) were observed; treatment was well-tolerated with no Grade 4 adverse events.

Conclusions:

• ONC201 monotherapy demonstrates durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
• The treatment is well-tolerated, suggesting potential as a therapeutic option for this challenging patient population.