Early increase in apparent diffusion coefficient predicts favorable response to Dordaviprone (ONC201) therapy in H3K27M-mutant diffuse midline glioma

Benison C Lau; Diala P Ajaero; Benjamin A Hoff; Ashley Pearson; Peter Sajjakulnukit; Jack Wadden; Tiffany Adam; Sunjong Ji; Adam L Green; Ali Nabavizadeh; Yue Cao; Madhava Aryal; Santhosh Upadhyaya; Andrea Franson; Stefanie Galban; Sriram Venneti; Bryan Federowicz; Mark A Shapiro; Timothy J Stuhlmiller; Costas Lyssiotis; Craig J Galban; Hemant A Parmar; Mohannad Ibrahim; Carl Koschmann

doi:10.1093/neuonc/noag164

Early increase in apparent diffusion coefficient predicts favorable response to Dordaviprone (ONC201) therapy in H3K27M-mutant diffuse midline glioma

Neuro Oncol. 2026 Jul 21:noag164. doi: 10.1093/neuonc/noag164. Online ahead of print.

Authors

Benison C Lau^{1

2}, Diala P Ajaero¹, Benjamin A Hoff³, Ashley Pearson¹, Peter Sajjakulnukit⁴, Jack Wadden¹, Tiffany Adam¹, Sunjong Ji¹, Adam L Green⁵, Ali Nabavizadeh⁶, Yue Cao⁷, Madhava Aryal⁷, Santhosh Upadhyaya¹, Andrea Franson¹, Stefanie Galban³, Sriram Venneti⁸, Bryan Federowicz⁹, Mark A Shapiro⁹, Timothy J Stuhlmiller⁹, Costas Lyssiotis⁴, Craig J Galban³, Hemant A Parmar³, Mohannad Ibrahim³, Carl Koschmann¹

Affiliations

¹ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
² Pediatric Neuro-Oncology Program, UPMC, Pittsburgh, PA, USA.
³ Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
⁵ Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado Anschutz School of Medicine, Children's Hospital Colorado, Aurora, CO, USA.
⁶ Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁷ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁹ xCures, Inc., Oakland, CA, USA.

PMID: 42482168
DOI: 10.1093/neuonc/noag164

Abstract

Background: Dordaviprone (ONC201) is the first FDA-approved therapy for H3K27M-mutant diffuse midline glioma (DMG). However, therapeutic response varies among patients, and no imaging biomarkers currently predict long-term benefit. Diffusion-weighted MRI and apparent diffusion coefficient (ADC) obtained during standard clinical imaging reflects tissue cellularity and necrosis, offering potential as an early response indicator.

Methods: Clinical and imaging data from patients treated with dordaviprone (n = 83) on completed studies underwent centralized neuroradiology review, ADC histogram analysis, and Functional Diffusion Mapping (fDM), which were compared and correlated to CSF tumor DNA (tDNA) and metabolomics when available. Final analysis included 38 patients receiving standardized dordaviprone dosing and treatment schedule.

Results: In the pre-progression cohort, early changes in volumetric or cross-sectional RAPNO criteria were not predictive of overall (OS) or progression-free survival (PFS). Importantly, in patients treated pre-progression with dordaviprone post-radiation, tumors with increased diffusion ADC (reduced cellularity) at cycle 3 demonstrated median OS of 732 days versus 360 days for those with decreased ADC (increased cellularity, p = 0.0149); with corresponding PFS of 334 versus 110 days (p = 0.0132).fDM analysis of spatio-temporal changes of ADC did not correlate with outcomes in a sub-cohort analysis but demonstrated predictive patterns in individual patient time course series. CSF metabolomics stratified by ADC change revealed differences in reductive stress metabolites among dordaviprone responders, linking ADC elevation to dordaviprone -driven metabolic effects.

Conclusion: Early increase in ADC correlates with improved response to dordaviprone in H3K27M-DMG and correlates with CSF metabolic changes, suggesting ADC warrants prospective validation as a biomarker.

Keywords: Apparent Diffusion Coefficient; Brain tumor; Diffuse Midline Glioma; Diffuse intrinsic Pontine Glioma; Diffusion-weighted imaging.

Plain language summary

Dordaviprone (ONC201)is the first FDA-approved treatment for recurrent H3K27M-mutant diffuse midline glioma, but patient responses vary and no imaging biomarkers currently predict benefit. Diffusion MRI [apparent diffusion coefficient (ADC)], which reflects tumor cellularity, is obtained during routine care. In patients treated with dordaviprone after radiation and before progression, early changes in tumor size did not predict survival. However, tumors showing increased ADC after two cycles were associated with longer overall survival and delayed progression. Anecdotal analyses of spinal fluid metabolites showed patterns consistent with dordaviprone’s expected biological effects, supporting further study of early ADC increase as a potential biomarker.