The U.S. Food and Drug Administration (FDA) has granted accelerated approval to dordaviprone (Modeyso) a protease activator, for adult and pediatric patients aged 1 year and older with diffuse midline glioma harboring an H3 K27M mutation who have progressive disease after prior therapy. This represents the first FDA approval of a systemic therapy for H3 K27M–mutant diffuse midline glioma.
Confirmatory Trials
Efficacy was evaluated in an integrated efficacy population of 50 adult and pediatric patients with recurrent H3 K27M–mutant diffuse midline glioma enrolled across five open-label, nonrandomized clinical trials conducted in the United States (ONC006 [ClinicalTrials.gov identifier NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131]). The efficacy population comprised patients who received single-agent dordaviprone for diffuse midline glioma harboring an H3 K27M mutation and had progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria. Patients were also at least 90 days post–radiation therapy, had an adequate washout period from prior anticancer therapies, a Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score of ≥ 60, and stable or decreasing corticosteroid use. Patients with diffuse intrinsic pontine glioma, primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were excluded.
The major efficacy outcome measure was overall response rate assessed by blinded independent central review according to RANO 2.0 criteria, with duration of response as a secondary outcome measure. The overall response rate was 22% (95% confidence interval [CI] = 12%–36%), and the median duration of response was 10.3 months (95% CI = 7.3–15.2 months). Among the 11 patients with objective responses, 73% had a duration of response lasting at least 6 months, and 27% had a duration of response lasting at least 12 months.
The dordaviprone prescribing information includes warnings and precautions for hypersensitivity, QTc interval prolongation, and embryofetal toxicity.
Recommended Dosage
For adults, the recommended dordaviprone dosage is 625 mg orally once weekly. For pediatric patients, the recommended dosage is based on body weight.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review. Dordaviprone received Orphan Drug, Rare Pediatric Disease, and Fast Track designations.
