FDA Approves the First Targeted Therapy for Glioma Brain Tumors: Vorasidenib

On 6 August 2024, the FDA (US Food and Drug Administration) approved a treatment for diffuse gliomas carrying certain isocitrate dehydrogenase (IDH) mutations, namely vorasidenib (Voranigo, Servier). This is a major development as the first targeted therapy approved for brain tumors with IDH mutations.

Vorasidenib will be used after surgery in adults and children aged 12 and over to treat IDH1- or IDH2-mutated grade 2 astrocytoma or oligodendroglioma. According to the FDA, surgery includes biopsy, subtotal resection, or total resection.

IDH1 mutations occur in approximately 80% of grade 2 gliomas, while IDH2 mutations are rarer, found in approximately 4%.

FDA-approved vorasidenib treatment does not include grade IV gliomas known as glioblastoma multiforme (GBM).

Brain Tumors and Gliomas: General Information

Brain tumors are the 12th most common cancer in Türkiye, with over 6 thousand new cases each year. Of these tumors, 30-35% are gliomas, a type of brain tumor arising from the brain’s supporting tissue cells. They can occur at any age but are most common in adults. Symptoms and treatment responses vary considerably. Standard treatments generally include surgery, radiation, and chemotherapy.

Gliomas arise from glial cells in the brain and are divided into subtypes according to cell type, location, and growth rate. Their types and general characteristics are:

1. Astrocytomas

Astrocytomas arise from star-shaped glial cells called astrocytes. They are divided into two main groups: low-grade (benign) and high-grade (malignant):

• Grade I (Pilocytic Astrocytoma): Usually occurs in children. It grows slowly and can generally be completely removed surgically.
• Grade II (Diffuse Astrocytoma): Grows slowly but may transform into a higher-grade tumor over time.
• Grade III (Anaplastic Astrocytoma): Grows faster and is aggressive. Treated with surgery, radiation, and chemotherapy.
• Grade IV (Glioblastoma Multiforme – GBM): The most aggressive and common type. It grows rapidly and spreads into surrounding brain tissue.

2. Oligodendrogliomas

Oligodendrogliomas arise from oligodendrocytes, cells that produce the myelin sheath around nerve cells. There are two main types:

• Grade II (Oligodendroglioma): Grows slowly and has a better prognosis.
• Grade III (Anaplastic Oligodendroglioma): More aggressive and faster-growing. Treatment generally includes surgery, radiation, and chemotherapy.

3. Ependymomas

Ependymomas arise from ependymal cells lining cavities in the brain and spinal cord. They can occur across different age groups:

• Grade I (Subependymoma): Grows slowly and is usually benign.
• Grade II (Ependymoma): Intermediate-grade and may respond to treatment.
• Grade III (Anaplastic Ependymoma): More aggressive and may be difficult to treat.

4. Mixed Gliomas

These tumors arise from both astrocytes and oligodendrocytes. Also called hybrid tumors, they are treated according to the predominant cell type.

Grading Gliomas

The World Health Organization (WHO) grades gliomas according to how rapidly they grow and spread:

• Grade I (Low-Grade): Slow-growing with clear boundaries. Generally easy to remove surgically.
• Grade II (Low-Grade): Slower-growing but may transform into higher-grade tumors over time.
• Grade III (High-Grade): Grows faster and spreads into surrounding brain tissue.
• Grade IV (High-Grade – Glioblastoma): The most aggressive, fastest-growing tumor type. It rapidly spreads into surrounding tissue and resists treatment.

These details show how diverse and complex gliomas are. Each type may have different treatments and disease courses, making personalized plans highly important.

How Does Vorasidenib Work?

Vorasidenib is a dual inhibitor of IDH1 and IDH2. These enzymes convert isocitrate, a metabolite involved in energy production, into alpha-ketoglutarate (α-KG). In some cancer cells, however, mutations may cause these enzymes to produce 2-hydroxyglutarate (2-HG) instead of α-KG, causing uncontrolled cell growth and division. By suppressing the mutant enzymes, vorasidenib reduces 2-HG production and may thereby stop cancer cell growth and division.

FDA Approval Based on INDIGO

The approval was based on the pivotal phase 3 INDIGO study, providing evidence of vorasidenib’s effectiveness and safety. A total of 331 patients were randomized to 40 mg vorasidenib daily (168 patients) or placebo (163 patients).

• After a median follow-up of 14.2 months, progression-free survival (PFS) in patients receiving vorasidenib was twice as long as with placebo: 27.7 versus 11.1 months, respectively (HR for disease progression or death, 0.39).
• Vorasidenib also significantly prolonged time to the next intervention (median not reached versus 17.8 months; HR, 0.26).

Adverse Effects

Grade 3 or higher adverse effects occurred in 22.8% with vorasidenib versus 13.5% with placebo. Grade 3 or higher alanine aminotransferase elevation occurred in 9.6% versus 0%, respectively. The most common vorasidenib adverse effects include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizures.

Dose

The recommended adult vorasidenib dose is 40 mg once daily until disease progression or unacceptable toxicity. For children aged 12 and over, the recommended daily dose is 40 mg at a body weight of ≥ 40 kg and 20 mg at < 40 kg.