On April 23, 2024, the U.S. FDA granted accelerated approval to tovorafenib (brand name Ojemda), a type II RAF kinase inhibitor, for the treatment of recurrent/refractory low-grade glioma in pediatric patients aged 6 months and older with BRAF fusions/rearrangements or V600 mutations. This approval marks the first systemic therapy specifically for this patient population.

Key efficacy data

Approval was based on the results of the FIREFLY-1 multicenter clinical trial (NCT04775485). The study included 76 patients who had previously received at least one line of systemic therapy. Exclusion criteria included:

• Co-occurring activating mutations in IDH1/2 or FGFR, etc.
• Confirmed or suspected type 1 neurofibromatosis (NF1)

Patients received oral tovorafenib once weekly (dose 290-476 mg/m², maximum 600 mg) until disease progression or unacceptable toxicity occurred. The primary endpoint showed:

• The objective response rate (complete response + partial response + minimal response) was 51% (39/76 cases, 95% CI: 40%-63%).
• The median duration of remission was 13.8 months (95% CI: 11.3 months to not evaluable).

Clinical application guide

Dosing regimen

• Recommended dose: 380mg/m2 once a week (maximum 600mg)
• Dosage form: Immediate-release tablets or oral suspension
• Precautions: Can be taken with food; the safe dosage for patients with a body surface area ≤ 0.3 m² has not yet been established.

Dose adjustment

The label provides dose adjustment guidelines for the following situations in particular：

• Bleeding event
• Skin toxicity
• Hepatotoxicity
• Concomitant use with potent inhibitors/inducers of CYP2C8, specific CYP3A substrates, and hormonal contraceptives.

Security features

Observed in 137 patients receiving treatment：

Common adverse events (≥30%)

• Skin related: skin rash (77%), hair discoloration (76%), dry skin (36%), acne-like dermatitis (31%)
• Systemic: fatigue (55%), fever (39%)
• Gastrointestinal tract: vomiting (50%), constipation (33%), nausea (33%)
• Infection: Viral infection (55%), upper respiratory tract infection (31%)

Level 3-4 adverse events

• Laboratory abnormalities: hypophosphatemia (25%), anemia (15%), elevated creatine kinase (11%)
• Clinical events: rash (12%), viral infection (7%), bleeding (5%)

Serious risk warning

• 45% of patients had serious adverse events, of which 9% were viral infections
• 7% of patients stopped taking the drug due to adverse events
• One case reported death from tumor bleeding
• Black box warnings include risks of bleeding, skin toxicity (including photosensitivity reactions), and hepatotoxicity.

Important notes

• May affect children's growth and development
• Has embryo-fetal toxicity.
• May affect reproductive function
• Patients with NF1-related tumors require special monitoring.

(Note: The efficacy data in this article is current as of May 16, 2024. For complete prescription information, please refer to the FDA website or the product's package insert.)

References

1. U.S. Food and Drug Administration: FDA accelerates approval of tovorafenib for pediatric low-grade gliomas with BRAF mutations. See drug information on the official FDA website.Accessed May 16, 2024.

Source of information： Original ASCO Post

For more related information, please refer to the guidelines on novel targeted therapies issued by the Drug Office of the Department of Health, Hong Kong: Medicines Office of the Hong Kong Department of Health.

See also The research progress of the School of Medicine of the University of Hong Kong on Brain Tumors in Children： Cancer Research, School of Medicine, University of Hong Kong.

Find out more about treatment information

The following are internal links related to the topic of this article. Welcome to browse to learn more.：

• The latest article of the United Cancer Center of Hong Kong (Map 1)
• Classification Information of the United Cancer Centre of Hong Kong