Treatment with the IDH1/2 inhibitor vorasidenib (AG-881) reduced the risk of progression or death by 61% compared with placebo for patients with grade 2 IDH-mutant glioma, according to findings from the INDIGO clinical trial published in the New England Journal of Medicine.1,2 Vorangio received FDA approval in August 2024.
Gliomas are a cancer that originate in the glia – the supporting cells of the brain – not the brain neurons themselves. Gliomas comprise about 80% of all malignant brain tumors. Some are slow-growing low-grade gliomas, while others are aggressive high-grade gliomas including glioblastomas that are difficult to remove and almost always recur.
Cancer results from abnormal genes or gene regulation. The cause of these changes can be environmental, spontaneous, or inherited. By identifying the genomic changes and knowing which genes are altered in a patient, cancer drugs that specifically attack that gene (or the later consequences of that gene) can be used to target the cancer. Two people with glioma for example, may not respond to treatment in the same way if their cancers are caused by different mutations. Because the development and spread of every cancer is driven by a unique set of abnormalities in that individual cancer’s genetic makeup, the genetic makeup of each glioma may be unique and vary from patient to patient. In other words, all gliomas are not the same, and they cannot be optimally treated using the same drug.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack cancer cells with specific abnormalities often leaving normal cells largely unharmed. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes. Precision cancer medicine requires molecular diagnostic testing, including DNA sequencing, to identify the cancer growth causing abnormalities in a cancer’s genome. This NGS “genomic testing” is typically performed on a biopsy sample of the cancer or the blood using a “liquid biopsy it tissue is not available. When the cancer growth causing abnormality is identified, a specific precision cancer medicine can identified or designed to attack the specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Until recently researchers did not believe NGS-biomarker testing was a viable strategy for brain tumors but there is emerging evidence that there may be targets in gliomas that could be blocked by precision medicines. It was recently determined that the BRAFV600 mutation is present in 3% of patients with high-grade gliomas and up to 60% of certain types of low-grade gliomas. BRAFV600 can be targeted with precision cancer medicines.
About Vorasidenib
Mutations in the IDH1 or IDH2 gene are now known to be present in some individuals with gliomas. These genes help cells make certain proteins, which are also called IDH1 and IDH2. Mutations in one of these genes can stop cells from maturing normally. The FDA has previously approved precision medicines that target IDH for other cancer types.
In the current study, 331 patients with low grade oligodendroglioma or astrocytoma and an IDH mutation were treated with oral vorasidenib or a matched placebo in 28-day cycles and directly compared. The median age of patients in the study was 40, and the average interval from last glioma surgery to treatment was 2.4 years.
At 18-months from treatment 60% of vorasidenib treated patients survived cancer free compared with 27% of those receiving the placebo. The 24-month cancer free survival rates were 51% for vorasidenib compared with 18% for placebo. Its important to realize however that may patients take months to respond to Vorangio and treatment is often stopped too early.
An expert commenting on the results at the 2023 ASCO Annual Meeting, Dr. Glenn Lesser, MD, stated “These results are quite striking, they’re statistically highly significant, and more important, they’re clinically very important. In select patients with low-grade glioma, we can potentially delay the use of these toxic chemotherapy and radiation for years, perhaps many years, and delay the toxicity.”
References
1. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. Published online June 4, 2023. doi:10.1056/NEJMoa2304194
2. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. J Clin Oncol. 2023;41(suppl 17):LBA1. doi:10.1200/JCO.2023.41.17_suppl.LBA1
