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New Targeted Therapy Drug Shows Promise for Brain Cancer Treatment
Brain cancer is a devastating disease that affects thousands of people every year, causing symptoms such as headaches, seizures, nausea, and cognitive impairment. Among the many types of brain tumors, gliomas are one of the most common and aggressive, with a low survival rate and few treatment options. However, a recent international study co-led by UCLA scientists has discovered a potential breakthrough in glioma treatment, using a new targeted therapy drug called vorasidenib.
Vorasidenib is a dual inhibitor of mutant IDH1/2, which blocks the formation and accumulation of 2-hydroxyglutaramate (2-HG), a metabolite that fuels the growth and maintenance of gliomas with IDH1 and IDH2 mutations. By inhibiting the abnormal enzymes that produce 2-HG, the drug can slow down the progression of the cancer and extend the time until chemotherapy and radiation become necessary. The study involved 331 patients aged 12 or older who had recurrent grade 2 glioma with IDH1 and IDH2 mutations and had undergone surgery to remove the tumor. Half of them were given vorasidenib, while the other half received a placebo.
The key findings of the study revealed that vorasidenib significantly improved the progression-free survival (PFS) of patients with gliomas, nearly doubling the median PFS from 11.1 months to 27.7 months. In addition, the drug reduced the risk of disease progression by 48% and enabled 85.6% of patients to delay their next treatment for 18 months or longer, compared to 83.4% who went for 24 months or more. The most common side effects of the drug were mild to moderate, such as nausea, fatigue, loss of appetite, and mood changes. However, there were no fatal adverse events associated with vorasidenib, and patients who switched from placebo to the drug also benefited from the treatment.
What makes vorasidenib a game-changer in glioma therapy is that it is the first drug developed specifically to treat brain cancer that has shown unequivocal efficacy in a randomized clinical trial. The drug is a brain penetration inhibitor that can pass through the blood-brain barrier, which has been a major barrier to developing effective targeted therapies for brain tumors. The blood-brain barrier is a protective mechanism that separates the brain from the bloodstream, preventing most drugs and molecules from entering the brain tissue. However, vorasidenib has proven to be effective in crossing the barrier and reaching the mutated cells that drive glioma growth, making it a breakthrough in brain cancer research.
The study’s co-senior author, Dr. Timothy Cloughesy, a professor of neuro-oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Center, said that vorasidenib could significantly improve the quality of life for glioma patients, especially younger adults who face the long-term effects of radiation and chemotherapy. “Having the ability to postpone radiation therapy to the brain with an effective therapy is really critical and very significant for this patient population,” he said. Moreover, the drug could pave the way for more targeted therapies to treat different types of brain tumors and neurological disorders.
The study was sponsored by Servier Pharmaceuticals, the manufacturer of vorasidenib, and published in the New England Journal of Medicine. Although the drug has not yet been approved by the FDA for clinical use, it is a promising step towards a better future for brain cancer patients. According to the American Brain Tumor Association, about 700,000 people in the US are living with a brain tumor, and nearly 17,000 die from it every year. Moreover, brain tumors are the leading cause of cancer-related death in children and young adults under 20 years old. Therefore, any progress in brain cancer research is crucial to improving the survival rates and quality of life of those affected by this devastating disease.
Summary:
The study demonstrated that vorasidenib can extend the amount of time for which people with a glioma subtype (recurrent grade 2 glioma with IDH1 and IDH2 mutations) receive treatment without their cancer getting worse and more than doubled progression-free survival compared to those who received a placebo. The drug has the potential to allow delays between periods of chemotherapy and radiation to crucially support patient populations. The drug is a brain penetration inhibitor and prevents the formation and accumulation of the oncometabolite 2-hydroxyglutaramate present in a tumor and believed to be responsible for the formation and maintenance of IDH-mutant gliomas. The most common side effects of the drug were mild to moderate, and there were no fatal adverse events associated with vorasidenib. The study is also the first clinical trial to test a targeted therapy drug developed specifically to treat brain cancer.
The study involved 331 people aged 12 years and older who had been diagnosed with recurrent grade 2 glioma with the IDH1 and IDH2 mutations and who had undergone brain tumor surgery. Patients taking Vorasidenib had more time until further treatment was required, up to 17 months, and the disease progressed in only 28% of patients who received vorasidenib, compared with 54% of those who received placebos. Further, 72% of patients in the vorasidenib group were still taking the drug and their disease had not progressed 30 months after the study began. Limited adverse side effects of vorasidenib were noted and lead to the conclusion that this is the first targeted treatment to show unequivocal efficacy in this population and sets a precedent for this disease.
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In an international study co-led by UCLA, scientists have shown that a new targeted therapy drug can extend the amount of time people with a glioma subtype receive treatment without their cancer getting worse. The finding suggests a possible new treatment option for people with the slow-growing but deadly brain tumor.
The team found that the drug vorasidenib more than doubled progression-free survival in people with recurrent grade 2 glioma with IDH1 and IDH2 mutations. Compared with people who received a placebo, those who took vorasidenib went almost 17 more months without their cancer getting worse, delaying the time before they needed to start chemotherapy and radiation.
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 article, recurrent grade 2 glioma with IDH1 and IDH2 mutations, tends to affect younger people, often in their 30s. The current standard treatment, a combination of radiation and chemotherapy, can cause neurological deficits that make it difficult 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 found in the early years of their professional life.
Dr. Timothy Cloughesy, 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 allows patients to go longer periods between chemotherapy and radiation could have a high 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 postpone radiation therapy to the brain with an effective therapy is really critical and very significant for this patient population.”
Vorasidenib is classified as a dual inhibitor of mutant IDH1/2, meaning that it prevents the formation and accumulation of the oncometabolite 2-hydroxyglutaramate, or 2-HG, which occurs when versions of two enzymes, IDH1 and IDH2, are genetically altered. present in a tumor. 2-HG is believed to be responsible for the formation and maintenance of IDH-mutant gliomas.
The study is also the first clinical trial to test a targeted therapy drug developed specifically to treat brain cancer.
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 cancer cells and healthy ones, targeted therapies only attack cancer cells with the mutated target and minimize damage to normal cells.
While there has been great progress in the use of targeted therapies to treat many types of cancer, the development of targeted therapies for brain tumors has been especially challenging due to the difficulty in crossing the blood-brain barrier. Vorasidenib is a brain penetration inhibitor, which means that it has the ability to cross the blood-brain barrier.
The study involved 331 people aged 12 years and older who had been diagnosed with recurrent grade 2 glioma with the IDH1 and IDH2 mutations and who had undergone brain tumor surgery. Of that group, 168 were randomized to receive vorasidenib and 163 received placebos.
Among those who received vorasidenib, the disease did not progress for an average of 27.7 months, much longer than the 11.1 months for those who received placebo. And among those who received vorasidenib, 85.6% went 18 months before their next treatment, while 83.4% went 24 months between treatments.
The disease progressed in only 28% of people who received vorasidenib, compared with 54% of those who received placebos. And as of September 2022, 30 months after the study began, 72% of patients 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 allowed a switch to vorasidenib. Investigators noted limited adverse side effects of vorasidenib. “This is the first targeted treatment to show unequivocal efficacy in this population and sets a precedent 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 the tumors in the study, which confirmed that there was benefit from 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 makes vorasidenib. The drug has not yet been approved by the FDA for clinical use.
https://www.sciencedaily.com/releases/2023/06/230605181002.htm
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