SUMMARY: Glioma is the most common neoplasm of the CNS in adults and originates from glial cells. It is estimated that in the US, 6 cases of gliomas are diagnosed per 100,000 people each year. Gliomas are very diffusely infiltrative tumors, with Glioblastoma being the most malignant type, where as Pilocytic astrocytomas are the least malignant brain tumors.
Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression resulting in the accumulation of oncometabolite 2-hydroxyglutarate, which prevents cellular differentiation. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle.
Almost all Grade 2 diffuse gliomas in adults are associated with IDH mutations and in the most recent update to the WHO classification, gliomas that have a mutation in IDH1 or IDH2 and an unbalanced translocation between chromosomes 1 and 19 (1p/19q-codeleted) are defined as oligodendrogliomas, whereas IDH-mutant gliomas without 1p/19q codeletion (1p/19q–non-codeleted) are defined as astrocytomas. IDH-mutant Grade 2 oligodendrogliomas and astrocytomas are slow and continuous in their growth pattern, infiltrate normal brain tissue, and eventually transform to aggressive tumors with accelerated tumor growth and neovascularization, which is reflected by the appearance of enhancement on contrast MRI. Diffuse Grade 2 gliomas with IDH mutation represent the most common malignant primary brain tumors diagnosed in adults younger than 50 years of age and are not curable with current therapies. They affect approximately 30,000 adults in the US and the mean age at diagnosis is 41 years and the appropriate treatment regimen remains unclear.
Treatment options for patients with Grade 2 glioma include surgery, chemotherapy, and radiotherapy. Complete surgical resection may not be feasible due to the anatomical location and growth pattern of the tumor. The timing of adjuvant therapy after surgery remains controversial and patients with low risk of early disease progression are often monitored. Radiotherapy alone following surgery prolongs the time to recurrence but does not increase Overall Survival, and may be associated with a reduction in neurocognitive function. Chemotherapy with concurrent radiation treatment improves Overall Survival but these tumors will eventually recur.
Vorasidenib is a dual inhibitor of the mutant IDH1 and IDH2 enzymes that crosses the blood-brain barrier, and has a favorable safety profile. In a perioperative trial, treatment with Vorasidenib resulted in more than 90% reduction in the concentration of the oncometabolite 2-hydroxyglutarate in resected tumor, which in turn was associated with reversal of gene expression and epigenetic changes typically associated with IDH mutation in glioma
INDIGO is a global, randomized, double-blind Phase III trial, conducted to assess the efficacy of Vorasidenib in patients with recurrent or residual IDH-mutant glioma. In this study, a total of 331 patients (N=331) were randomly assigned to receive Vorasidenib 40 mg orally once daily (N=168) or a matching placebo (N=163) in 28-day cycles. Enrolled patients had residual or recurrent Grade 2 IDH-mutant glioma, and had undergone no previous treatment other than surgery, with the median interval between the last glioma surgery and randomization being 2.4 years. The two treatment groups were well balanced with respect to baseline characteristics. The median patient age was 40 years and all the patients had undergone brain tumor surgery previously, with 21.5% of the patients having undergone two or more tumor surgeries before enrollment. The numbers of astrocytomas and oligodendrogliomas were similar in the two treatment groups. The tumor size at baseline (determined on the basis of the longest diameter) was at least 2 cm in more than 80% of patients in each treatment group. Randomization was stratified according to locally determined chromosome 1p/19q status (codeleted or non-codeleted) and baseline tumor size (longest diameter 2 cm or more, or less than 2 cm). Patients with high-risk features (such as disease with contrast enhancement on MRI or brain-stem involvement) or uncontrolled disease-related symptoms were excluded. The Primary end point was imaging-based Progression Free Survival as assessed by Blinded Independent Review Committee. Key Secondary end point was the time to the next anticancer intervention. Crossover to Vorasidenib from placebo was permitted upon confirmation of imaging-based disease progression.
At a median follow-up of 14.2 months, 68.3% of patients were continuing to receive Vorasidenib or placebo. The PFS was significantly improved in the Vorasidenib group as compared with the placebo group, with a PFS of 27.7 months versus 11.1 months respectively (HR for disease progression or death=0.39; P<0.001). The Key Secondary end point of the time to the next intervention was also significantly improved in the Vorasidenib group as compared with the placebo group (HR=0.26; P<0.001). The benefit with Vorasidenib was seen across all subgroups independent of tumor type (astrocytoma or oligodendroglioma), and the time since the last surgery. Adverse events of Grade 3 or higher occurred in 23% of the patients who received Vorasidenib and in 13.5% of those who received placebo. Approximately 9% of the patients who received Vorasidenib had an increased hepatic alanine aminotransferase level of Grade 3 or higher.
It was concluded that in patients with Grade 2 IDH-mutant glioma, Vorasidenib significantly improved Progression Free Survival and delayed the time to the next intervention. The authors added that even though the current trial showed single-agent activity of Vorasidenib in patients with previously untreated WHO Grade 2 glioma, additional studies will be necessary to define the role of Vorasidenib, as a single agent, or as part of combination therapy regimens, in patients with glioma who have received cancer therapy previously or who present with WHO grade 3 or 4 disease.
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. N Engl J Med 2023; 389:589-601
