A New Targeted Drug for Brain Tumors: Vorasidenib Draws Attention at ASCO 2023

Brain tumors are the 12th most common cancer type in Turkey, with more than 6 thousand new cases annually. 30-35% are gliomas, tumors arising from the brain's supporting glial cells. They can occur at any age but are most common in adults. Types are generally classified by cell type, location and grade, meaning how quickly they grow and spread. Symptoms and treatment responses vary widely. Standard treatment generally includes surgery, radiation and chemotherapy.

Tumors are described by grade, based on growth and spread. Gliomas have four grades:

1. Grade I (Low Grade): The least aggressive tumors, growing slowly with clearer boundaries that make surgical removal easier. Grade I gliomas generally occur in children.

2. Grade II: Still low grade, but growing somewhat faster with less defined boundaries. They tend to develop into higher-grade tumors over time.

3. Grade III: High-grade, more aggressive tumors that grow rapidly and invade surrounding normal brain tissue.

4. Grade IV (Glioblastoma): The most aggressive, fastest-growing gliomas, also called GBM or GMB-IV. They rapidly invade surrounding tissue and are generally treatment-resistant.

Along with grading, the most important information about glioma biology comes from IDH mutation status .

Isocitrate dehydrogenase (IDH) plays an important role in normal cell metabolism. Its two main types are IDH1 and IDH2. The genes encoding these enzymes can harbor mutations, which are particularly common in brain tumors and certain leukemias.

IDH1 mutations are common in a substantial proportion of brain tumors, particularly low-grade gliomas and secondary glioblastomas. IDH2 mutations are less common, generally occurring less frequently than IDH1 mutations.

For example, approximately 80% of grade 2 gliomas have IDH1 mutations, while only around 4% have IDH2 mutations. IDH1/2 mutations therefore help explain tumor genetics and offer potential treatment targets. Tumor IDH status can be tested by immunohistochemistry (IHC), PCR (polymerase chain reaction) or NSG (comprehensive genomic sequencing).

For patients with a particular glioma type carrying IDH1 and IDH2 mutations, the oral targeted drug vorasidenib may offer hope as an alternative to chemotherapy and radiation, which have more side effects.

Mechanism of Action

Vorasidenib inhibits both IDH1 and IDH2 enzymes. They normally convert isocitrate into alpha-ketoglutarate (α-KG), a metabolite supporting energy production. In some cancer cells, mutant enzymes instead produce 2-hydroxyglutarate (2-HG) rather than α-KG, promoting uncontrolled growth and division. By inhibiting these mutant enzymes, vorasidenib reduces 2-HG production and may stop cancer cells growing and dividing.

The First Potential Targeted Drug for Grade 2 Gliomas

INDIGO , a phase 3 trial, evaluated vorasidenib in 331 patients at 77 centers across North America, Europe and the Middle East.

On June 4, the study was presented at ASCO 2023 and published concurrently in NEJM .

• Patients were aged 12 to 80 with recurrent or residual grade 2 oligodendroglioma or astrocytoma harboring IDH1 or IDH2 mutations.
• Patients were randomized to vorasidenib 40 mg daily or placebo in 28-day cycles. At the September 2022 cutoff, 226 of the 331 participants (68.3%) remained on treatment.
• Among patients receiving vorasidenib, median progression-free survival (PFS) was 27.7 months, compared with 11.1 months with placebo. This suggests patients receiving vorasidenib delayed progression by an average of 16.6 months longer. The risk of progression or death was 61% lower than with placebo (hazard ratio 0.39, P < 0.0001).

• Common side effects include elevated liver enzymes, fatigue, headache, diarrhea and nausea. Grade 3 or 4 alanine aminotransferase elevations occurred in 9.6% of vorasidenib patients, compared with none receiving placebo.

Vorasidenib therefore offers an oral targeted treatment with the potential to reduce progression risk by 61%. This notable efficacy could substantially change treatment.

It may alter the natural course of diffuse glioma while preserving quality of life, offering hope for patients with IDH-mutant grade 3 gliomas and IDH-mutant grade 2 tumors at high risk of early progression.

This new oral drug represents important progress against brain tumors. As researchers continue documenting effectiveness and safety, regulatory approval for wider use may follow. It offers hope of changing treatment and helping glioma patients preserve quality of life.