Source: Journal of Clinical Oncology
URL: https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10017
Dordaviprone demonstrates modest but clinically meaningful activity in recurrent H3 K27M-mutant diffuse midline gliomas, with objective response rates of 16.7% in adults and 9.1% in pediatrics using strict RANO criteria. The drug shows an acceptable safety profile with durable responses (median 15.1 months in adults) and represents the first targeted therapy option for this universally fatal malignancy.
Study Design & Population
Study Type: Two prospective Phase 1/2 single-arm trials (ONC013 Arm B, ONC014 Arm F)
- Adult cohort (ONC013): 30 patients, median age 32 years (range 21-66)
- Pediatric cohort (ONC014): 11 patients, median age 14 years (range 11-19)
- Tumor location: Majority non-brainstem midline tumors (63% both cohorts)
- Prior therapy: Most patients had one prior recurrence (73% adults, 66% pediatrics)
- Dosing: 625 mg weekly (adults), weight-based dosing (pediatrics)
Key Findings
- Adult ORR: 16.7% (95% CI: 5.6-34.7%) with 5 partial responses
- Pediatric ORR: 9.1% by strict RANO criteria (18.2% radiographic responses)
- Duration of response: Median 15.1 months in adults (7.5 months to not reached)
- Time to response: 3.8 months (adults), 1.9 months (pediatrics)
- Notable pediatric response: One patient achieved >95% tumor regression lasting 8.5 months
- Safety profile: Grade ≥3 treatment-related AEs in 10% (adults) and 9.1% (pediatrics)
Clinical Implications
- First demonstration of single-agent activity in H3 K27M-mutant gliomas using prospectively defined response criteria
- Confirms previous pooled analyses showing reproducible anti-tumor activity across age groups
- Establishes dordaviprone as a treatment option for recurrent disease where no standard therapies exist
- Durable responses support continued development in this rare, uniformly fatal tumor type
Limitations
- Small sample sizes limit statistical power, particularly in pediatric cohort (n=11)
- Single-arm design prevents comparison to historical controls or standard care
- DIPG exclusion limits applicability to most common pediatric brainstem glioma
- Response assessment relied on investigator interpretation rather than central review