Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort
Yazmin Odia1, Matthew D Hall1, Timothy Francis Cloughesy2
1Department of Neuro-Oncology, Miami Cancer Institute (MCI), Baptist Health South Florida, Miami, Florida, USA.
Background:
Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported.
Methods:
Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR).
Results:
Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness.
Conclusions:
H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.
Insights
Dordaviprone (ONC201) shows activity in H3 K27M-mutant diffuse gliomas, even those outside the brain midline. This offers hope for patients with these rare, aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Clinical Trials
Background:
- Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are aggressive brain tumors with limited treatment options.
- The WHO classification initially restricted H3 K27M diagnoses to midline gliomas, but these mutations can occur elsewhere.
- Dordaviprone (ONC201) is an investigational drug showing promise in recurrent H3 K27M-mutant DMG.
Purpose of the Study:
- To evaluate the activity of ONC201 in patients with non-midline H3 K27M-mutant diffuse gliomas.
- To assess the overall response rate (ORR) of ONC201 in this patient population.
Main Methods:
- Five patients with recurrent non-midline H3 K27M-mutant diffuse gliomas were enrolled in clinical trials.
- Eligibility criteria included measurable disease, adequate performance status, and time since radiation.
- The primary endpoint was the overall response rate (ORR) assessed by RANO criteria.
Main Results:
- Two of five patients achieved a confirmed objective response (one complete, one partial) by RANO criteria.
- One patient had stable disease, and another was deemed nonmeasurable.
- A responding patient experienced improvements in mobility and alertness.
Conclusions:
- H3 K27M-mutant diffuse gliomas can occur in the non-midline cerebrum.
- ONC201 demonstrates activity against H3 K27M-mutant gliomas regardless of their location within the CNS.
