Dr Sumrall on the Clinical Efficacy of ONC201 in H3K27M -Mutant Diffuse Midline Gliomas

Ashley Sumrall, MD, FACP, clinical assistant professor, medicine, University of North Carolina at Chapel Hill, medical oncologist, section chief, Neuro-Oncology, Atrium Health, Levine Cancer Institute, discusses the clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas.

The investigational small molecule ONC201 functions as a dopamine receptor D2 antagonist, and has shown preclinical activity when treating gliomas and other solid tumors through dopaminergic activation integrated stress response, as well as inactivation of AKT and ERK. Patients with H3K27M-mutant diffuse midline glioma have achieved promising outcomes when treated with ONC201, Sumrall begins. Furthermore, prior research has shown that patients with disease affecting the thalamus experience better responses with ONC201 due to an enriched presence of dopamine receptors in this structure, Sumrall notes. 

According to results from a phase 2 pilot study (NCT02525692), ONC201 treatment without molecular stratification did not improve progression-free survival compared with historical controls in patients with recurrent, bevacizumab (Avastin)–naive, IDH1/2 wild-type glioblastoma. However, the agent showed signs of anti-tumor activity in 2 of 4 patients with H3K27M mutations who were enrolled in the 2 glioblastoma arms of this trial. Subsequent findings from a follow-up study showed that treatment with ONC201 prolonged responses among multiple patients with H3K27M-mutant disease in a mixed cohort of several ongoing studies (n = 18).

To further elucidate the efficacy of and mechanism underlying responses to ONC201 in this population investigators evaluated data from a completed phase 1 study (NCT03416530) and a completed expanded access study (NCT03134131), Sumrall details. Results show that patients treated with ONC201 post-initial radiation, but before recurrence, exhibited a median overall survival (OS) of 21.7 months, whereas those treated following disease recurrence had a median OS of 9.3 months. The agent was deemed well tolerated with minimal adverse effects, Sumrall adds.

The mechanistic insights from this study reveal that ONC201 disrupts integrated metabolic and epigenetic pathways, thereby addressing the pathognomonic reduction in H3K27me3. Overall, this comprehensive study supports ONC201 as a potential monotherapy for improving outcomes in H3K27M-mutant diffuse midline glioma beyond radiation.