William G. Nelson, MD, PhD Photo by Joe Rubino

PROGRESS IN TREATING benign and malignant brain tumors has been hard to come by, so the recent approval of Voranigo (vorasidenib) by the Food and Drug Administration (FDA) for a subset of these tumors is welcome news indeed.

Voranigo is effective in treating brain tumors containing defective IDH1 or IDH2 genes, identified in tumor specimens removed during brain surgery. The drug is designed to selectively target the abnormal enzymes produced as a result of these gene defects.

Gliomas are tumors that arise in the brain or spinal cord from glial cells, cells that do not transmit nerve impulses as neurons do. In all, gliomas represent some 30% of all central nervous system tumors. A glioma diagnosis tends to be heralded by symptoms such as new-onset seizures, severe headaches or new neurologic deficits. Magnetic resonance imaging (MRI) or computed tomography (CT) scanning typically ensues, with surgery (when feasible) and biopsy yielding the formal diagnosis.

Glial tumors can be classified by their location in the brain, by the non-neuronal cells they most resemble under a microscope, and by pathologic grade. Grade I tumors exhibit benign behavior and have the best prognosis, grade II tumors can grow slowly but often recur, while grade III and IV tumors act more aggressively and malignantly and have the worst prognosis. Grade IV gliomas are usually referred to as glioblastomas. Surgery, radiation therapy and chemotherapy can all play a role in treatment, but each needs to be carefully tailored to balance potential benefits with significant risks of side effects and complications.

Gliomas can also be classified using tumor gene sequencing, defining disease subsets for targeted treatments. Defective IDH1 or IDH2 genes have been found in 60% to 90% of low-grade gliomas and in some 12% of glioblastomas. The defective IDH1 and IDH2 genes encode mutant enzymes that produce D-2-hydroxyglutarate, a substance that corrupts multiple regulatory pathways within glial cells, driving them to become tumor cells.

Voranigo possesses two properties well suited to treat gliomas with IDH1 or IDH2 mutations. First, the drug suppresses the production of D-2-hydroxyglutarate, stopping its promotion of tumor growth. Second, after being taken orally, the drug readily reaches the brain and spinal cord. Many drugs, including most anticancer drugs, are unable to penetrate into the brain or spinal cord, regardless of whether they are ingested, injected under the skin or infused into veins. Instead, the drugs encounter a semipermeable “blood-brain barrier” that allows ready passage of glucose, vital nutrients, oxygen and carbon dioxide, but keeps out infections, antibodies and toxins, ensuring the health of nerve cells while insulating them from damage. Discovering and designing drugs that can traverse the blood-brain barrier to stop tumor cells, while inflicting limited harm on normal nerve cells, has historically proven incredibly difficult—one of the major challenges limiting the effectiveness of drug treatment for brain tumors.

In a phase III trial, patients with residual or recurrent grade II gliomas (astrocytoma or oligodendroglioma) carrying mutant IDH1 or IDH2 genes, following surgery as the only treatment, received Voranigo. In the trial, 331 patients were randomized to receive either Voranigo or a placebo orally each day for 28-day treatment cycles until the disease progressed or unacceptable side effects were encountered. Using repeated brain imaging to detect disease progression, researchers found that worsening of glioma was 61% less likely for those on Voranigo than for those taking the placebo. Even more remarkably, 85.6% of Voranigo-treated patients had not needed any further treatment for glioma 18 months after starting the treatment. The drug was fairly well tolerated, with a dose reduction or discontinuation necessary for only 14.4% of those treated. The most common side effects were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea and seizure. Reviewing these data, the FDA approved Voranigo for systemic therapy of grade II gliomas for patients ages 12 and up with IDH1 or IDH2 mutations on Aug. 6, 2024.

This is a huge step for patients confronting low-grade brain tumors and for the multidisciplinary care teams seeking to help them. Hopefully, this advance can serve as the first of many such steps as additional targeted antitumor drugs that can penetrate the blood-brain barrier are discovered and developed.

William G. Nelson, MD, PhD, is the director of the Johns Hopkins Kimmel Cancer Center in Baltimore.