A groundbreaking clinical trial has demonstrated that vorasidenib, the first targeted therapy developed specifically for brain cancer, significantly delays disease progression in patients with IDH-mutant low-grade gliomas. The international INDIGO study, involving 331 patients across 10 countries, showed that the oral medication more than doubled progression-free survival compared to placebo, offering new hope for a patient population with limited treatment options.
Significant Improvement in Disease Control
The phase 3 trial revealed that patients receiving vorasidenib experienced a median progression-free survival of 27.7 months, compared to just 11.1 months for those receiving placebo. Among vorasidenib recipients, 85.6% went for 18 months before their next treatment, while 83.4% remained treatment-free for 24 months. Disease progression occurred in only 28% of patients receiving vorasidenib, compared to 54% of those on placebo.
"This is the first targeted treatment that shows unequivocal efficacy in this population and is precedent-setting for this disease," said Dr. Timothy Cloughesy, professor of neuro-oncology at UCLA's David Geffen School of Medicine and co-senior author of the study.
The trial was stopped early after a planned analysis showed clear benefit for the vorasidenib group, with all placebo participants offered access to the active drug. As of September 2022, 30 months after the study began, 72% of patients in the vorasidenib group were still taking the drug without disease progression.
Addressing Critical Unmet Medical Need
Low-grade gliomas predominantly affect younger patients, often in their 30s and 40s, who are otherwise healthy and in the early stages of their careers or starting families. The current standard treatment combining radiation and chemotherapy can cause significant neurological deficits, including difficulties with learning, memory, concentration, and decision-making.
"We're always concerned about the delayed effects of radiation," explained Dr. 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 an effective therapy is really critical and very meaningful to this population of patients."
The cognitive changes resulting from radiation and chemotherapy can be particularly debilitating for this young, active patient population. "Patients with these tumors are young and could live for many years with the disease," noted Dr. Cloughesy. "At this stage of their lives, they are active and working hard at their jobs and may be starting families."
Novel Mechanism of Action
Vorasidenib is classified as a dual inhibitor of mutant IDH1/2, designed to prevent the formation and accumulation of the onco-metabolite 2-Hydroxyglutarate (2-HG). This metabolite occurs when genetically altered versions of IDH1 and IDH2 enzymes are present in tumors and is thought to be responsible for the formation and maintenance of IDH-mutant gliomas.
Unlike traditional chemotherapy that affects both cancerous and healthy cells, vorasidenib specifically targets cancer cells with the mutated proteins while minimizing damage to normal cells. Crucially, the drug is brain-penetrant, meaning it can cross the blood-brain barrier—a significant challenge in developing therapies for brain tumors.
IDH1 and IDH2 mutations, first identified in gliomas in 2008, are now known to occur in approximately 80% of low-grade gliomas. The mutant proteins produce 2-HG, which can alter gene behavior and affect cells in various ways.
Excellent Safety Profile
The study demonstrated that vorasidenib is generally well tolerated by patients. The most common side effects included fatigue, headache, and diarrhea. Some patients developed increased levels of liver enzymes indicating liver damage, but these changes were reversible according to the researchers.
"This treatment is generally very well tolerated by patients," said study co-leader Dr. Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center, who presented the findings at the American Society of Clinical Oncology (ASCO) annual meeting.
Establishing New Standard of Care
The positive results have generated significant excitement within the neuro-oncology community. "The findings establish a new standard of care for these patients," said Dr. Rimas Lukas, who specializes in treating brain cancer at Northwestern University's Lurie Comprehensive Cancer Center.
Dr. Mark Gilbert, chief of the Neuro-Oncology Branch in NCI's Center for Cancer Research, expects the findings to be transformative. The INDIGO trial could be "transformative for the management of patients with low-grade glioma and the field of neuro-oncology," said Dr. Gilbert, who was not involved in the study.
Patient Community Response
The results have generated considerable hope within the patient community. "The INDIGO trial has been a hot topic in our community and has caused a great deal of hope and excitement," said Nestelynn Gay, who founded a Facebook group for people with low-grade gliomas that has grown to about 4,000 members. She was diagnosed with the disease a decade ago at age 37.
"Having a new study that focuses on low-grade glioma is huge for our community, because little to no pharmaceutical research has been done specifically for us," Ms. Gay explained.
Regulatory Pathway and Future Directions
The FDA granted vorasidenib fast-track designation in March, and Servier Pharmaceuticals, the drug's manufacturer, is working to establish a timeline for submission of an approval application. The positive results are expected to spur additional research, including studies to identify which patients might benefit most from the drug and whether gliomas might develop resistance to the therapy.
Vorasidenib is also being investigated in combination with other therapies, including a current study combining it with pembrolizumab (Keytruda) for treating some gliomas. Researchers are also exploring its potential against higher-grade gliomas with IDH1 or IDH2 mutations.
The research team's systematic approach—confirming IDH1 and IDH2 as promising drug targets, designing a brain-penetrant drug, and conducting preliminary studies before the large randomized trial—may serve as a model for future brain tumor drug development.
"We hope this approach might help other people think about how to develop drugs for glioblastoma and other brain tumors," said Dr. Cloughesy. "These findings are just the beginning. We need to take the research forward, because this drug is not a cure for the disease."
