Selective DRD2 Antagonist and ClpP Agonist ONC201 in a Recurrent Non-midline H3 K27M-mutant Glioma Cohort

Abstract 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 WHO CNS Tumors Classification defined H3K27M 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 H3K27M-mutant DMG. Activity of ONC201 in non-midline H3K27M-mutant diffuse gliomas has not been reported. Methods Patients with recurrent non-midline H3K27M-mutant diffuse gliomas treated with ONC201 were enrolled on 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG), Karnofsky/Lansky performance score (KPS/LPS) ≥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 two, however one deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. Conclusions H3K27M-mutant diffuse gliomas occasionally occur in nonmidline cerebrum. ONC201 exhibits activity in H3K27M-mutant gliomas irrespective of CNS location.