Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201
BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.
Medical Subject Headings
Adolescent; Adult; Antineoplastic Agents (therapeutic use); Brain Neoplasms (drug therapy, genetics, pathology); Child; Child, Preschool; Female; Follow-Up Studies; Glioma (drug therapy, genetics, pathology); Heterocyclic Compounds, 4 or More Rings (therapeutic use); Histones (genetics); Humans; Imidazoles; Male; Mutation; Prognosis; Pyridines; Pyrimidines; Receptors, Dopamine D2 (chemistry); Survival Rate; Young Adult
Journal of neuro-oncology
Digital Object Identifier (DOI)
Chi, Andrew S.; Tarapore, Rohinton S.; Hall, Matthew D.; Shonka, Nicole; Gardner, Sharon; Umemura, Yoshie; Sumrall, Ashley; Khatib, Ziad; Mueller, Sabine; Kline, Cassie; Zaky, Wafik; Khatua, Soumen; Weathers, Shiao-Pei; Odia, Yazmin; Niazi, Toba N.; Daghistani, Doured; Cherrick, Irene; Korones, David; Karajannis, Matthias A.; Kong, Xiao-Tang; Minturn, Jane; Waanders, Angela; Arillaga-Romany, Isabel; Batchelor, Tracy; Wen, Patrick Y.; Merdinger, Krystal; Schalop, Lee; Stogniew, Martin; Allen, Joshua E.; Oster, Wolfgang; and Mehta, Minesh P., "Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201" (2019). Neurology. 1454.