On April 23, 2024, tovorafenib (Ojemda) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for patients aged 6 months and older who have relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 mutation.1 Tovorafenib is a type II RAF kinase inhibitor.
Supporting Efficacy Data
Approval was based on findings in 76 patients who had at least one prior systemic therapy in the multicenter FIREFLY-1 trial (ClinicalTrials.gov identifier NCT04775485). Patients with tumors harboring additional activating molecular alterations (eg, IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 (NF1) were excluded. Patients received oral tovorafenib at 290 mg/m2 to 476 mg/m2, to a maximum dose of 600 mg once weekly until disease progression or unacceptable toxicity.
Response, defined as complete response (none observed), partial response, or minor response on blinded independent central review, was achieved in 39 patients (51%, 95% confidence interval [CI] = 40%–63%). Median duration of response was 13.8 months (95% CI = 11.3 months to not estimable).
How It Is Used
The recommended dose of tovorafenib is 380 mg/m2 orally once weekly, to a maximum dose of 600 mg 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 up to 0.3 m2 has not been established.
Product labeling provides instructions on dosage modification (including dose reduction) for adverse reactions including hemorrhage, skin toxicity, and hepatotoxicity. Labeling provides instructions on concomitant use with moderate and strong CYP2C8 inhibitors and inducers, certain CYP3A substrates, and hormonal contraceptives.
Safety Profile
Safety was evaluated in 137 patients receiving tovorafenib in FIREFLY-1. The most common adverse events of any grade were rash (77%), hair color changes (76%), fatigue (55%), viral infection (55%), vomiting (50%), headache (45%), hemorrhage (42%), pyrexia (39%), dry skin (36%), constipation (33%), nausea (33%), dermatitis acneiform (31%), and upper respiratory tract infection (31%). The most common grade 3 or 4 adverse events included rash (12%), viral infection (7%), and hemorrhage (5%). The most common grade 3 or 4 laboratory abnormalities were decreased phosphate (25%), decreased hemoglobin (15%), and increased creatine phosphokinase (11%).
Serious adverse events occurred in 45%, most commonly viral infection (9%), pneumonia (4%), and sepsis (4%). Adverse events led to treatment discontinuation in 7%. A fatal adverse event of tumor hemorrhage was reported in one patient (1%).
The labeling for tovorafenib includes warnings/precautions for hemorrhage, skin toxicity (including photosensitivity), hepatotoxicity, effect on growth, embryofetal toxicity, and NF1-associated tumors. It may impair fertility in males and females.
REFERENCE
1. U.S. Food and Drug Administration: 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. Accessed May 16, 2024.
