NCCN Adds Dordaviprone in Glioma to Clinical Guidelines

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology have added dordaviprone (Modeyso) as a category 2A single-agent treatment option for pediatric and adult patients with recurrent or progressive diffuse high-grade glioma harboring an H3 K27M mutation.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," said Kelvin Tan, MB BCh, MRCPCH, chief medical affairs officer of Jazz Pharmaceuticals, in a press release. "We are proud to bring [dordaviprone] to patients in the US as the first treatment option for recurrent H3 K27M-mutant diffuse midline glioma, representing a meaningful shift in the treatment landscape for patients and their families."

Dordaviprone earned FDA accelerated approval in this patient population on August 6, 2025.² The approval was supported by data from 5 nonrandomized clinical trials involving 50 patients with recurrent H3 K27M-mutant diffuse midline glioma. In this analysis, the overall response rate was 22% with a median duration of response (DOR) of 10.3 months. Seventy-three percent of patients achieved a DOR of 6 months, and 27% achieved a DOR of 12 months.

“There has been a huge need for better treatments, but it's also been very difficult to figure out if treatments are actually efficacious, because one of the challenges is that it's very hard to look at response rates. Following [patients] for progression-free survival and overall survival is pretty unreliable. You really need a randomized study to do that,” said Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber Cancer Center and professor of neurology at Harvard Medical School, in an interview with Targeted Oncology.

“This study that was done was different from most studies in that it's not a standard trial with a fixed end point. It was the accumulation of patients from 5 different trials who had measurable disease, so there was a way to see if the drug did something or not to the tumor,” Wen explained. “There has been some criticism that it's not just 1 trial with a fixed end point, but there was no way to do that. This [study] was done in conjunction with the FDA to have 50 patients that you could evaluate and see if the drug did anything or not.”

Regarding safety, 49 of 50 patients experienced at least 1 treatment-emergent adverse event (AE), with the most frequently reported being fatigue (46%), nausea (36%), and headache (32%).³ Treatment-related AEs of any grade were observed in 60% of patients, including fatigue (34%), nausea (18%), and decreased lymphocyte levels (14%). Grade 3 treatment-related AEs were seen in 20% of patients, with fatigue (10%) being the only one occurring in more than 2 individuals. No grade 4 treatment-related AEs or deaths were reported.

Dordaviprone is continuing to be evaluated in the ongoing phase 3 ACTION trial looking at safety and clinical benefit.¹ The study has an estimated enrollment of 450 patients and a prospective completion date of August 2026.⁴

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 11, 2025. https://tinyurl.com/ahpwuh2m

2. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. News release. US FDA. August 6, 2025. Accessed September 11, 2025. https://tinyurl.com/kkjddc32

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

4. ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study) (ACTION). ClinicalTrials.gov. Updated August 26, 2025. Accessed September 11, 2025. https://clinicaltrials.gov/study/NCT05580562