NCCN Adds Dordaviprone to Clinical Practice Guidelines in H3K27M-Mutant Diffuse High-Grade Glioma

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology to include dordaviprone (Modeyso) as a category 2A single agent for the treatment of pediatric and adult patients with recurrent or progressive diffuse high-grade glioma harboring an H3K27M mutation.¹

In August 2025, the FDA granted accelerated approval to dordaviprone for the treatment of adult and pediatric patients at least 1 year of age with diffuse glioma who harbored an H3K27M mutation and experienced disease progression after prior therapy.² Dordaviprone is a protease activator and is the first systemic therapy for H3K27M-mutant diffuse midline glioma that has been FDA approved.

Continued approval for the respective indication could be contingent upon verification and description of clinical benefit in the phase 3 ACTION confirmatory trial (NCT05580562).¹

“The rapid addition of [dordaviprone] to the NCCN Guidelines—in both the Pediatric Central Nervous System Cancers and Central Nervous System Cancers guidelines—reflects the urgency of the unmet need that patients are faced with when diagnosed with this devastating and aggressive brain tumor,” Kelvin Tan, MBBCh, MRCPCH, chief medical affairs officer of Jazz Pharmaceuticals, the developer of dordaviprone, stated in a news release. “We are proud to bring [dordaviprone] to patients in the United States as the first treatment option for recurrent H3K27M-mutant diffuse midline glioma, representing a meaningful shift in the treatment landscape for patients and their families.”

The accelerated approval of dordaviprone was supported by an integrated efficacy analysis that included 50 patients with recurrent H3K27M-mutant diffuse midline glioma, who were selected from 5 open-label studies based on prespecified eligibility criteria. These included the phase 2 ONC006 (NCT02525692), phase 2 ONC013 (NCT03295396), phase 1 ONC014 (NCT03416530), phase 2 ONC018 (NCT03134131), and expanded-access ONC016 (NCT05392374) studies.^1,2

In this analysis, the overall response rate (ORR) assessed by blinded independent central review (BICR) per Response Assessment in Neuro-Oncology 2.0 criteria was 22% (95% CI, 12%-36%). Additionally, the median duration of response was 10.3 months (95% CI, 7.3-15.2) in those who showed a response, with 73% of patients maintaining a response for at least 6 months and 27% for at least 12 months.

Additional efficacy data from the pooled analysis revealed that the corticosteroid response rate was 46.7% (n = 7 of 15; 95% CI, 21.3%-73.4%), and the median time to corticosteroid response was 3.7 months (range, 1.9-5.6).³

Regarding safety, 376 patients were evaluated from 4 open-label studies.¹ Serious adverse effects (SAEs) were observed in 33% of patients. SAEs reported in at least 2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%). Furthermore, the most common AEs occurring in at least 20% of patients treated with dordaviprone included fatigue, headache, vomiting, nausea, and musculoskeletal pain.

Of note, in the pooled analysis, patients were at least 90 days post-radiation therapy, had an adequate washout period before receiving anticancer therapies, a Karnofsky performance status/Lansky performance status of 60 or greater, and stable or decreasing corticosteroid use.² Patients were not permitted to have diffuse intrinsic pontine glioma, primary spinal tumors, atypical histology, or cerebrospinal fluid dissemination.

Among the 50 patients included in the pooled analysis, 28.6% of patients were 40 years of age and older, 20.5% were White, and 22.2% were male.³ Of note, 24.2% of patients had a primary tumor in the thalamus, and 24.4% had less than 2 target lesions.

References

1. Modeyso (dordaviprone) included in National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for H3 K27M-mutant diffuse glioma. News release. Jazz Pharmaceuticals. September 9, 2025. Accessed September 9, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/modeysotm-dordaviprone-included-national-comprehensive-cancer
2. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. FDA. August 6, 2025. Accessed September 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma
3. 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