Hope for Lethal Brain Tumors: Targeted Therapy Delays Glioma Progression

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A multinational study led by UCLA scientists revealed that a newly developed targeted therapy medicine has the potential to extend the duration of successful treatment for persons diagnosed with a specific subtype of glioma, avoiding cancer progression.

This remarkable discovery suggests a potential therapy option for patients suffering from this slow-growing but lethal brain tumor.

‘A leap forward in glioma treatment with vorasidenib therapy that can significantly delay cancer progression #vorasidenib #BrainTumor’

The researchers discovered that the medicine vorasidenib more than quadrupled the amount of time that people with recurrent grade 2 glioma with IDH1 and IDH2 mutations were free of disease progression.

When compared to those given a placebo, those given vorasidenib had an additional 17 months before their cancer deteriorated, essentially deferring the need for chemotherapy and radiation therapy.

The results were published in the New England Journal of Medicine and presented today at the annual meeting of the American Society of Clinical Oncology in Chicago.

The type of glioma studied in the paper, recurrent grade 2 glioma with IDH1 and IDH2 mutations, tends to affect younger people, often those in their 30s.

The current standard treatment, a combination of radiation and chemotherapy, can cause neurological deficits that make it hard for patients to learn, remember new things, concentrate or make everyday decisions - all of which can be especially challenging for people who have young families or are in the early years of their professional lives.

Longer the Duration of Treatment, Greater the Impact

Dr. Timothy Cloughesy, a professor of neuro-oncology at the David Geffen School of Medicine at UCLA and co-senior author of the study, said the availability of a treatment that enables patients to go for longer periods of time between chemotherapy and radiation treatments could have a major impact.

"We're always concerned about the delayed effects of radiation," said Cloughesy, who is also a member of the UCLA Jonsson Comprehensive Cancer Center. "Having the ability to hold off on getting radiation therapy to the brain with effective therapy is really critical and very meaningful to this population of patients."

Vorasidenib is classified as a dual inhibitor of mutant IDH1/2, meaning that it prevents the formation and accumulation of the oncometabolite 2-Hydroxyglutarate or 2-HG, that occurs when genetically altered versions of two enzymes, IDH1 and IDH2, are present in a tumor. 2-HG is thought to be responsible for the formation and maintenance of IDH-mutant gliomas.

The study is also the first clinical trial to analyze a targeted therapy drug specifically developed to treat brain cancer.

Targeted Therapy Breakthrough Offers New Hope in Glioma Treatment

Targeted therapies are designed to target specific molecules that are involved in the growth and spread of cancer cells. Unlike chemotherapy and other therapies that can affect both cancerous and healthy cells, targeted therapies only attack cancer cells with the mutated target while minimizing damage to normal cells.

While there has been great progress in using targeted therapies to treat many types of cancer, the development of targeted therapies for brain tumors has been especially challenging because of the difficulty of getting through the blood-brain barrier. Vorasidenib is a brain-penetrant inhibitor, which means that it has the ability to cross the blood-brain barrier.

The study involved 331 people aged 12 and older who had been diagnosed with recurrent grade 2 glioma with the IDH1 and IDH2 mutations and who had undergone brain tumor surgery. From that group, 168 were randomly assigned to receive vorasidenib, and 163 received placebos.

Among those who received vorasidenib, the disease did not progress for an average of 27.7 months, significantly longer than the 11.1 months for those who received the placebo. And among those who received vorasidenib, 85.6% went for 18 months before their next treatment, while 83.4% went for 24 months between treatments.

The disease progressed in just 28% of people receiving vorasidenib, compared to 54% of those receiving placebos. And as of September 2022, which was 30 months after the study began, 72% of patients who were in the vorasidenib group were still taking the drug and their disease had not progressed.

For patients who were originally in the placebo group whose cancer began to progress during the study, doctors permitted a switch to vorasidenib. The researchers observed limited adverse side effects from vorasidenib. "This is the first targeted treatment that shows unequivocal efficacy in this population and is precedent-setting for this disease," Cloughesy said.

Benjamin Ellingson, director of the UCLA Brain Tumor Imaging Laboratory and a member of the Jonsson Cancer Center, was a key participant in the research that led to the clinical trial.

He was involved in the radiographic evaluation of tumors in the study, which confirmed that there was a benefit of the targeted therapy. The study's first author is Dr. Ingo Mellinghoff of Memorial Sloan-Kettering Cancer Center. The co-senior author is Dr. Patrick Wen of the Dana-Farber Cancer Institute.

The study was sponsored by Servier Pharmaceuticals, which manufactures vorasidenib. The drug has not yet been approved by the FDA for clinical use.

Reference:

1. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma - (https:www.nejm.org/doi/full/10.1056/NEJMoa2304194)

Source: Eurekalert