Duke brain tumor researchers are part of earliest collaborations that led to the development of the drug, shown to more than double progression-free survival
The FDA has approved a new targeted drug specifically for brain tumors called low-grade gliomas. The drug, vorasidenib, was shown in clinical trials to delay progression of low-grade gliomas that had mutations in the IDH1 or IDH2 genes.
“Although there have been other targeted therapies for the treatment of brain tumors with the IDH mutation, [this one] has been one of the most successful in survival prolongation of brain tumor patients,” said Darell Bigner, MD, PhD, the E. L. and Lucille F. Jones Cancer Distinguished Research Professor and founding director of the Preston Robert Tisch Brain Tumor Center at Duke.
In clinical trials, progression-free survival was estimated to be 27.7 months for people in the vorasidenib group versus 11.1 months for those in the placebo group.
Bigner, Katherine Peters, MD, PhD, professor of neurology and neurosurgery, and others at the Duke Brain Tumor Center played pivotal roles in the development and approval of the drug: Bigner in the early collaborations with Johns Hopkins University that led to the discovery of the IDH mutation, and Peters, more recently, as lead investigator in the clinical trials.
Patents developed from the early collaborations were licensed to industry through the Duke University Office for Translation & Commercialization, making this the seventh drug currently on the market with Duke intellectual property roots.
Drs. Bigner and Peters as well as Hai Yan, MD, PhD (formerly the Henry S. Friedman Distinguished Professor of Neuro-Oncology at Duke) answered questions about the work that led to vorasidenib.
Discovery
How did the discovery of the IDH gene mutation contribute to the overall understanding of brain cancer?
Bigner: The discovery of the mutant IDH gene is one of the most important discoveries in neuro-oncology. The IDH mutation has been incorporated by the World Health Organization into the rapid and accurate diagnosis and classification of astrocytic, oligodendroglial, and glioblastoma multiforme brain tumors. Never before has there been a single gene mutation that contributed so greatly to classification. Most importantly, it was immediately recognized that the IDH mutation could be targeted with drugs to treat the group of patients that had malignant brain tumors that expressed the IDH mutation.
Describe the collaboration between Johns Hopkins and Duke that led up to the development of this drug.
Bigner: Perhaps the most important collaboration between Johns Hopkins and Duke came in the work that led to the discovery of the IDH mutation. The National Cancer Institute had established a program in which genome sequencing of all the major cancers was to be done and decided that glioblastoma would be the first cancer that they investigated. The Johns Hopkins and Duke group decided to also perform complete genome sequencing of glioblastoma. The NCI did not do complete genome sequencing. Using the Duke material, the Johns Hopkins group sequenced the entire genome that could be done at that time, in 2008. The sequencing at that time was very laborious, rather than in the automated manner that can be done now. By doing almost complete genome sequencing, the Johns Hopkins and Duke group discovered the IDH mutation. The collaboration with Johns Hopkins was strengthened when [we] recruited Dr. Hai Yan [to Duke] in 2003. Dr. Yan had just completed a 5-year period as a post-doctoral research fellow at Johns Hopkins with Dr. Bert Vogelstein in Cancer Molecular Genetics.
Yan: Subsequent research from these teams produced numerous publications that further elucidated the pathological roles of IDH mutations, leading to the reclassification of gliomas in the WHO CNS classification. This body of work ultimately paved the way for the development of targeted therapies, culminating in the approval of [vorasidenib]. This collaboration … exemplifies the power of interdisciplinary and inter-institutional cooperation in driving scientific discovery and innovation in cancer treatment.
Can you briefly explain mechanism of action of vorasidenib?
Yan: Mutations in the IDH1 or IDH2 genes result in elevated levels of the oncometabolite D-2HG, disrupting normal cellular functions and contributing to tumorigenesis. Vorasidenib selectively binds to the mutated IDH1 and IDH2 enzymes, inhibiting their activity and thereby reducing the production of D-2HG. This inhibition helps to restore normal cellular processes, reduce tumor cell proliferation, and promote the differentiation of cancer cells.
How does the development and approval of vorasidenib affect the broader future of cancer research and treatment? Are there plans to study vorasidenib in combination with other treatments or in different types of brain cancers?
Yan: The development and approval of vorasidenib represent a significant milestone in the field of oncology, particularly in the treatment of brain cancers. It validates the approach of targeting specific genetic mutations with precision therapies and reinforces the importance of personalized medicine in oncology. This success is likely to inspire further research into targeting other genetic mutations and metabolic pathways in various cancers.
Bigner: There are indeed plans to explore the potential of vorasidenib beyond its current indications. Researchers are investigating its use in combination with other therapies, such as immune checkpoint inhibitors, to enhance therapeutic efficacy. Additionally, studies are being planned or are already under way to assess the effectiveness of vorasidenib in treating other types of brain cancers, solid tumors and leukemia with IDH mutations. The ongoing research aims to expand the therapeutic applications of vorasidenib and optimize its use in various clinical settings, potentially benefiting a broader spectrum of cancer patients.
What the Clinical Research Showed
What were the outcomes of the clinical trial for vorasidenib?
Peters: The INDIGO clinical trial was a phase 3 trial of vorasidenib, an oral inhibitor of mutant IDH1/2 that can readily cross the blood-brain barrier, versus placebo in patients with mutant IDH1/2 glioma. Treatment with vorasidenib significantly improved progression-free survival (27.7 months vorasidenib vs. 11.1 for placebo).
The key secondary endpoint was time to next intervention, which means the time to needing chemotherapy, radiation therapy, or more surgery. For patients receiving placebo, the median time to next intervention was 17.8 months, but for patients receiving vorasidenib, the median time to next intervention has not yet been reached. Thus, patients on vorasidenib could significantly delay chemotherapy, radiation therapy, or more surgery. Most importantly, the vorasidenib was well tolerated with only 3.6% of patients needing to stop the drug because of an adverse event.
What about quality of life for patients on the trial?
Peters: Results showed that throughout the study, patients with IDH mutant low grade glioma had a good quality of life, and it was preserved throughout the study. Patients on vorasidenib were able to maintain their cognitive abilities and did not have any decline in their quality of life or cognition.
How might this drug influence future research and development in neuro-oncology?
Peters: At Duke, we are conducting studies of vorasidenib on patients with high-grade tumors and enhancing disease. Most of these studies look at combining vorasidenib with immunotherapy. It will be exciting to see what will happen with the INDIGO study's long-term outcomes.
What does the approval of vorasidenib mean for the treatment landscape of low-grade gliomas?
Peters: It is exciting to have a drug specifically targeted for these patients by inhibiting the mutant IDH enzyme. With vorasidenib being orally available, well-tolerated, and does not impair quality of life or cognition, we can extend people’s lives and delay the use of treatments such as radiation therapy and chemotherapy. I am so thankful to all the patients who participated in the groundbreaking study and for paving the way for future patients.