FDA Grants Accelerated Approval to Tovorafenib for Patients With Relapsed or Refractory BRAF-Altered Pediatric Low-Grade Glioma

On April 23, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to tovorafenib for patients aged 6 months and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion, rearrangement, or a BRAF V600 mutation. This approval was based on results from the phase 2 FIREFLY-1 trial. 

In this open-label, single-arm trial, 76 patients with relapsed or refractory pediatric low-grade glioma harboring an active BRAF alteration who received at least 1 prior line of systemic therapy were enrolled to receive tovorafenib once weekly based on body surface area (290 mg/m² to 476 mg/m²) until disease progression or unacceptable toxicity. Patients were required to have documented evidence of radiographic progression and at least 1 measurable lesion. Patients with tumors harboring additional activating alterations or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded from trial enrollment. The major efficacy outcome measure was overall response rate (ORR), defined as the proportion of patients with complete, partial, or minor response. Duration of response (DOR) was a key secondary efficacy outcome measure. 

At analysis, ORR was 51% and DOR was 13.8 months. The most common adverse reactions occurring in ≥30% of patients included rash, hair color change, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis, acneiform, and upper respiratory tract infection. The most common grade 3/4 laboratory abnormalities occurring in >2% of patients included 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 dose of tovorafenib based on body surface area is 380 mg/m² (600 mg/m² maximum) orally once daily with or without food until disease progression or unacceptable toxicity. The recommended dose for patients with body surface area <0.32 m² has not been established. 

This is the first FDA approval of a systemic therapy for patients with pediatric low-grade glioma with BRAF rearrangement. 

Source:

 FDA grants accelerated approval to tovorafenib for patient with relapsed or refractory BRAF-altered pediatric low-grade glioma. Published online: April 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patient-relapsed-or-refractory-braf-altered-pediatric