FDA Grants Accelerated Approval to Tovorafenib for Pediatric Patients With BRAF-Mutated LGG


Tovorafenib is the first systemic therapy to be approved for the treatment of pediatric patients who have low-grade glioma with BRAF rearrangements or fusions.

X-ray scan of brain -- Image credit: Alex Mit | stock.adobe.com

Image credit: Alex Mit | stock.adobe.com

About the Trial

Trial Name: A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)

ClinicalTrials.gov ID: NCT04775485

Sponsor: Day One Biopharmaceuticals, Inc.

Completion Date (Estimated): June 10, 2024

The FDA has granted an accelerated approval to tovorafenib (Ojemda; Day One Biopharmaceuticals, Inc) for the treatment of pediatric patients aged 6 months and older with relapsed or refractory low-grade glioma (LGG) characterized by a BRAF fusion or rearrangement, or BRAF V600 mutation. With this accelerated approval, tovorafenib is the first systemic therapy to be approved for the treatment of pediatric patients with LGG with BRAF rearrangements, including fusions, according to the FDA.1

The FDA also notes that the recommended dose for tovorafenib is a once-weekly, oral dose of 380 mg/m2—with a maximum recommended dose of 600 mg, also administered orally once a week—that can be administered either with or without food, until disease progression or intolerable toxicity.

The approval came after positive results from the multicenter, open-label, single-arm clinical trial, FIREFLY-1 (NCT04775485), which evaluated the efficacy and safety of tovorafenib (dose range: 290 to 476 mg/m2 based on body surface area; maximum dose of 600 mg) in 76 pediatric patients with LGG that have a lab-detected activated BRAF alteration who have received at least 1 prior line of systemic therapy.1

According to investigators, the major efficacy outcome measure of overall response rate was met, with patients achieving an ORR of 51% (95% CI: 40, 63). Additionally, the median duration of response was 13.8 months (95% CI: 11.3, not estimable).1

In addition to tovorafenib, the FDA has also previously approved dabrafenib (Tafinlar; Novartis) plus trametinib (Mekinist; Novartis) to treat pediatric patients with LGG with a BRAF V600E mutation who require systemic therapy; however, this indication is for patients who are 1 year of age and older. Liquid formulations of the drug were also approved by the FDA, making this combination the first BRAF/MEK inhibitor to be developed in a formulation that can be administered to patients as young as 1 year of age.2

Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. Prior to pediatric indications, the inhibitor was approved by the FDA for several indications in adults. Additionally, dabrafenib is a potent, selective inhibitor of some mutated forms of the protein kinase BRAF V600 mutations, that was previously approved as both a monotherapy and combination therapy for several indications in adult patients.3

“It is more important than ever to test for genetic mutations in patients living with LGG,” said Roger Packer, MD, senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital, in a press release. “This FDA approval may offer new hope to pediatric patients living with BRAF V600E LGG. This has the potential to change the way health care providers treat these pediatric patients, offering a significant advancement compared to chemotherapy.”2

The approval for dabrafenib and trametinib came after results from the phase 2/3 clinical trial, TADPOLE (NCT02684058), which randomly assigned pediatric patients to receive either the combination regimen or chemotherapy. Patients who received dabrafenib plus trametinib achieved a statistically significant improvement in ORR of 47%, compared with 11% in the chemotherapy group. Additionally, the median progression-free survival at a median follow-up period of 18.9 months was 20.1 months with the combination therapy compared with 7.4 months with chemotherapy.2

“Pediatric cancer research is vital to uncover new treatment methods for a population,” said Eric Bouffet, MD, FRCPC, principal investigator of the TADPOLE clinical trial, in the press release. “Developing targeted therapies based on the unique genetic features of a patient’s tumor is the future of pediatric cancer care.”2

In the FIREFLY-1 trial, the most common adverse events reported by patients receiving tovorafenib were rash, changes in hair color, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. Further, the most common grade 3 or 4 laboratory abnormalities were decreases in phosphate, hemoglobin, albumin, lymphocytes, leukocytes, potassium, and sodium, as well as increases in creatinine phosphokinase, alanine aminotransferase, and aspartate aminotransferase.1

1. US Food & Drug Administration. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. News release. April 23, 2024. Accessed April 26, 2024. https://bit.ly/3JWtiMB
2. Antrim, A. Dabrafenib, Trametinib Combination Receives FDA Approval for Pediatric Low-Grade Glioma with BRAF V600E Mutation. Pharmacy Times. March 17, 2023. Accessed April 26, 2024. https://www.pharmacytimes.com/view/dabrafenib-trametinib-combination-receives-fda-approval-for-pediatric-low-grade-glioma-with-braf-v600e-mutation
3. Antrim, A. Expert: Consider Oral Chemotherapies for Pediatric Patients With Low-Grade Gliomas. Pharmacy Times. April 14, 2021. Accessed April 26, 2024. https://www.pharmacytimes.com/view/expert-consider-oral-chemotherapies-for-pediatric-patients-with-low-grade-gliomas
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