Dr Cloughesy on the FDA Approval of Dordaviprone for Diffuse Midline Glioma

“[Diffuse midline glioma] is a particularly difficult tumor to manage. Having a therapy available is just a huge win for our field."

Timothy F. Cloughesy, MD, professor and director in the Department of Neurology, Neurological Services, and the Neuro-Oncology Program; a physician in the Department of Neurology; a member of the Brain Research Institute; a member of Cancer Molecular Imaging, Nanotechnology, and Theranostics; and a member of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center, discussed the significance of the FDA approval of dordaviprone (Modeyso) for the treatment of patients with diffuse midline glioma harboring an H3K27M mutation.

On August 6, 2025, the FDA granted accelerated approval to dordaviprone for the treatment of patients with H3K27M-mutant diffuse midline glioma who experience disease progression following prior therapy. This regulatory decision was based on findings from a pooled analysis of the open-label, nonrandomized, phase 2 ONC006 (NCT02525692), phase 2 ONC013 (NCT03295396), phase 1 ONC014 (NCT03416530), phase 2 ONC018 (NCT03134131), and expanded-access ONC016 (NCT05392374) studies.

Diffuse midline glioma is a challenging tumor to manage effectively, Cloughesy began, noting that the availability of an active therapeutic option for these patients represents a substantial advancement for the field. When efficacious treatments like dordaviprone emerge, they may inspire continued efforts to develop novel therapies for patients with primary brain tumors, which are characterized by an overall poor prognosis, he explained.

The studies conducted thus far with dordaviprone in this population have primarily consisted of trials evaluating single-agent therapy in the recurrent disease setting, according to Cloughesy. In these studies, patients were closely monitored to assess evidence of tumor progression, tumor regression, and treatment tolerability. In the context of single-arm studies, objective tumor shrinkage is the most robust indicator of drug activity, as these tumors do not spontaneously regress, he noted. Observing a reduction in tumor volume following administration of the investigational agent provides strong evidence that the therapeutic intervention is exerting a direct antitumor effect, he emphasized.

Conversely, if the only observation were stable disease (SD), it would be critical to establish the tumor’s growth trajectory prior to study entry, Cloughesy added. If the lesion had been progressing, continued growth would be anticipated in the absence of an effective therapy, he stated. However, if the tumor was not actively growing at baseline, then prolonged SD during treatment could be erroneously attributed to the investigational agent rather than reflecting the tumor’s natural history, he cautioned.

Therefore, the key considerations in interpreting the data from these studies are determining which patients experience objective tumor regression, the duration of response, and the time required to document evidence of tumor shrinkage, Cloughesy reported. These parameters provide the most meaningful early signals of therapeutic efficacy, he reiterated. In this case, precisely such evidence of activity was observed, Cloughesy concluded.