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. 2024 May 3;26(Supplement_2):S165-S172.
doi: 10.1093/neuonc/noae021.

Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort

Yazmin Odia  1 , Matthew D Hall  1 , Timothy Francis Cloughesy  2 , Patrick Y Wen  3 , Isabel Arrillaga-Romany  3 , Doured Daghistani  1 , Minesh P Mehta  1 , Rohinton S Tarapore  4 , Samuel C Ramage  4 , Joshua E Allen  4
Affiliations

Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort

Yazmin Odia et al. Neuro Oncol. .

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 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.

Keywords: ClpP; DRD2; H3 K27M-mutant glioma; ONC201; non-midline H3 K27M-mutant glioma.

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Conflict of interest statement

Y.O.: DSMB (unpaid) for Actuate Therapeutics, Oncoceutics, GammaTile; Trial support by BMS, Novocure, Chimerix, Karyopharm, VBI Therapeutics, MIMIVAX, and CNS Pharmaceuticals. No financial conflicts of interests. M.D.H.: Honorarium from IBA, Treasurer PTCOG-NA (unpaid), Pediatric Subcommittee Co-Chair PTCOG (unpaid), and PCG Executive Council Representative for MCI (unpaid). M.P.M.: Consulting fees from Karyopharm, Kazia Therapeutics, Sapience, Zap, Mevion, Xoft; Board of Directors Oncoceutics; Stock in Chimerix. P.W.: Research Support: Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, VBI Vaccines, Advisory Board/Consultant: Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccine. R.S.T., S.C.R., and J.E.A.: Employees and shareholders of Chimerix.

Figures

Figure 1.
Figure 1.
Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas: change in tumor measurement over time by RANO criteria. Tumor measurements over time based on (A) RANO high-grade glioma (RANO-HGG)* and (B) RANO low-grade glioma (RANO-LGG) criteria. Enrollment cutoff: February 27, 2020; data cutoff: May 31, 2021. Only patients with measurable target-enhancing lesions at both baseline and post-baseline assessments as assessed by the local investigator were included. BICR = blinded independent central review; RANO = response assessment for neuro-oncology; SPD = sum of products of perpendicular diameters (target-enhancing lesions per BICR).*One patient did not have baseline measurable disease per BICR assessment.
Figure 2.
Figure 2.
ONC201 responder case studies. Brain MRI over time shown for an adult case with complete response (A) and pediatric case with partial response* (B) treated with ONC201. *For the pediatric case (2B), the best change in TL area achieved >50% reduction necessary for PR; however, a new lesion at this timepoint detected by BICR resulted in an overall best response of SD by HGG-RANO. BICR = blinded independent central review; CR = complete response; HGG = high-grade glioma; LGG = neuro-oncology low-grade glioma; NA = not applicable; PR = partial response; RANO = response assessment for neuro-oncology; TL = target lesion.
See this image and copyright information in PMC

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