Tovorafenib Approved for BRAF-Altered Pediatric Low-Grade Glioma

The FDA has granted accelerated approval to tovorafenib (Ojemda™, Day One Biopharmaceuticals, Inc.) for patients six months of age or older with relapsed or refractory pediatric low-grade glioma (LGG) possessing a BRAF fusion, rearrangement, or BRAF V600 mutation.  

What they studied: Efficacy was measured in the FIREFLY-1 trial (NCT04775485), a phase 2, multicenter, open-label, single-arm study of 76 patients with relapsed or refractory pediatric LGG with an activating BRAF alteration who had received at least one line of prior systemic therapy. Patients received tovorafenib based on body surface area (BSA) ranging from 290 mg/m2 to 476 mg/m2, up to a maximum dose of 600 mg/m2, once weekly until they experienced disease progression or unacceptable toxicity.

Key inclusion criteria required the patients to have documented evidence of radiographic progression and at least one measurable lesion. Patients were excluded if they harbored any additional activating molecular alterations or a known or suspected diagnosis of neurofibromatosis type 1.

The primary efficacy end point measured was overall response rate, as defined by the accumulation of patients with a complete response, partial response, or minor response, via Blinded Independent Central Review (BICR) based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria. An additional secondary end point measured was duration of response.

What they found: The accumulated overall response rate was 51%, and the median duration of response was 13.8 months.

Adverse events: The most common adverse events experienced in ≥30% of 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 experienced in >2% of patients receiving tovorafenib 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.

Instructions: The recommended dosage based on BSA is 380 mg/mtovorafenib orally, once weekly, with or without food until disease progression or intolerable toxicity. Tovorafenib has a maximum recommended dosage of 600 mg. Tovorafenib is available as an immediate release tablet or as an oral suspension. There has not been an established recommended dosage for patients with BSA less than 0.3 m2.

For More Information

Kilburn LB, Khuong-Quang DA, Hansford JR, et al (2024). The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med, 30(1):207-217. DOI:10.1038/s41591-023-02668-y

Clinicaltrials.gov (2023). A study to evaluate DAY101 in pediatric and young adult patients with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). NLM identifier: NCT04775485.

Ojemda™ (tovorafenib) prescribing information (2024). Day One Biopharmaceuticals, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217700s000lbl.pdf

US Food and Drug Administration (2024). FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric

Image credit: Jensflorian. Licensed under CC BY-SA 4.0

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