On April 23, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the type II RAF inhibitor tovorafenib (Ojemda) for patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 mutation.
This represents the first FDA approval of a systemic therapy for the treatment of patients with pediatric low-grade glioma with BRAF rearrangements, including fusions.
FIREFLY-1
Efficacy was evaluated in 76 patients enrolled in FIREFLY-1 (ClinicalTrials.gov identifier NCT04775485), a multicenter, open-label, single-arm trial in patients with relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy. Patients were required to have documented evidence of radiographic progression and at least one measurable lesion. Patients with tumors harboring additional activating molecular alterations (eg, IDH1/2 or FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded. Patients received tovorafenib based on body surface area (range = 290–476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall response rate, defined as the proportion of patients with complete response, partial response, or minor response by blinded independent central review based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria. Additional efficacy outcome measures included duration of response. The overall response rate was 51% (95% confidence interval [CI] = 40%–63%) and median duration of response was 13.8 months (95% CI = 11.3 months to not estimable).
The most common adverse reactions (≥ 30%) in patients receiving tovorafenib were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. The most common grade 3 or 4 laboratory abnormalities (> 2%) were decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.
The recommended tovorafenib dose based on body surface area is 380 mg/m2 orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food until disease progression or intolerable toxicity. Tovorafenib is available as an immediate-release tablet or as an oral suspension. A recommended dosage for patients with a body surface area of less than 0.3 m2 has not been established.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The application was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials. This application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.
