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ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma
Isabel Arrillaga-Romany1, Sharon L Gardner2, Yazmin Odia3
1Massachusetts General Hospital, Boston, MA.
Purpose:
Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG.
Methods:
Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review.
Results:
The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred.
Conclusion:
ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
Insights
ONC201 monotherapy demonstrated durable efficacy in recurrent H3 K27M-mutant diffuse midline glioma (DMG). This well-tolerated treatment showed clinically meaningful responses in patients with this aggressive brain tumor.
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.
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