FDA Approves Dordaviprone for Diffuse Midline Glioma

The FDA has granted accelerated approval to dordaviprone (Modeyso) for the treatment of adult and pediatric patients at least 1 year of age with diffuse midline glioma harboring an H3K27M mutation who have progressive disease following prior therapy.1

Dordaviprone, a protease activator, is the first systemic therapy to be FDA approved for H3K27M-mutant diffuse midline glioma.

The agent was examined in an integrated efficacy population composed of 50 pediatric and adult patients with recurrent H3K27M-mutant diffuse midline glioma who received dordaviprone monotherapy across 5 open-label, nonrandomized clinical trials conducted in the United States: the phase 2 ONC006 (NCT02525692), phase 2 ONC013 (NCT03295396), phase 1 ONC014 (NCT03416530), phase 2 ONC018 (NCT03134131), and expanded-access ONC016 (NCT05392374) studies. All patients had progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma criteria.

Overall response rate (ORR) per blinded independent central review served as the major efficacy outcome measure in pooled data between the 5 trials. Duration of response (DOR) was a secondary outcome measured. The ORR was 22% (95% CI, 12%-36%), and the median DOR was 10.3 months (95% CI, 7.3-15.2). Of the 11 patients who achieved objective responses, 73% reached a DOR of at least 6 months, and 27% had a DOR of at least 12 months.

"There needs to be awareness from our colleagues that this is a therapeutic option for...patients, and an opportunity for us to provide benefit [through] tumor control, in addition to potential improvement in neurological function associated with the tumor shrinkage," Timothy Cloughesy, MD, a professor and director of the Department of Neurology, Neurological Services, and the Neuro-Oncology Program; a physician in the Department of Neurology; and a member of the Brain Research Institute at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California, shared in an interview with OncLive®. "[It is] critical for colleagues to understand and know about the value [of this agent] and the biomarker that needs to be evaluated for this, [and be] ready to use this therapy when it's appropriate for the patient."

All patients included in the pooled analysis had undergone radiation therapy at least 90 days prior to enrollment, had an adequate washout period from prior anticancer treatments, had a Karnofsky performance status or Lansky performance status of at least 60, and had stable or decreasing corticosteroid use. Patients were excluded if they had primary spinal tumors, diffuse intrinsic pontine glioma, cerebrospinal fluid dissemination, or atypical histologies.

Additional findings from the pooled analysis published in the Journal of Clinical Oncology in 2024 showed that the median time to response was 8.3 months (range, 1.9-15.9).2 Furthermore, among 15 evaluable patients, 7 achieved a 50% or greater corticosteroid dose reduction, translating to a rate of 46.7% (95% CI, 21.3%-73.4%). Moreover, 20.6% of evaluable patients (n = 6/34) achieved an improved performance score (95% CI, 8.7%-37.9%).

In total, 20.0% of patients experienced grade 3 treatment-related treatment-emergent adverse effects (TEAEs), among which fatigue was the most common (10%). No grade 4 treatment-related TEAEs, treatment discontinuations, or deaths were reported.

Notably, the dordaviprone prescribing information includes warnings and precautions for QTc interval prolongation, hypersensitivity, and embryo-fetal toxicity.1

"This is a particularly difficult tumor to manage," Cloughesy concluded. "Having [a treatment] that's available is a huge win for our field. When successful therapies come through like this, we hope that others will continue to pursue these new therapies in patients with primary brain tumors who have poor prognoses. However, we need the opportunity and successes like this to help people push forward to consider developing drugs for primary brain tumors."

References

1. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. FDA. August 6, 2025. Accessed August 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma
2. Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma. J Clin Oncol. 2024;42(13):1542-1552. doi:10.1200/JCO.23.01134