Servier’s Vorasidenib: Bridging a 20-Year Gap in IDH-Mutant Low-Grade Glioma Treatment, Paving the Way as the First Targeted Therapy

Phase III INDIGO trial

Vorasidenib is an oral medication that effectively inhibits both the IDH1 and IDH2 enzymes. It can cross the blood-brain barrier and is known for its potent and reversible action. Previously, the FDA recognized its significance by granting it breakthrough therapy designation for treating IDH1/IDH2-mutant low-grade glioma. More recently, the FDA has granted vorasidenib a fast-track designation for the treatment of patients in this specific population.

The results of the INDIGO trial, which investigated the use of vorasidenib, were presented at the ASCO annual meeting and published simultaneously in The New England Journal of Medicine. Vorasidenib exhibited a delay in disease progression and demonstrated good tolerability. These findings from the INDIGO trial mark a substantial advancement in the treatment of patients diagnosed with Grade II glioma with IDH mutations.

The study enrolled 331 eligible patients, ranging from 16 to 71 years old, across 10 countries. These patients had Grade II gliomas and IDH mutations. The study was randomized, double-blind, and placebo-controlled. Participants were assigned to receive either a daily oral dose of vorasidenib or a placebo in 28-day cycles. The vorasidenib arm consisted of 168 patients, while the placebo arm included 163 patients.

The primary endpoint of the study was to assess progression-free survival, which was determined by reviewing brain magnetic resonance imaging scans conducted centrally. The key secondary objective was to measure the time until the next treatment. In cases where confirmed disease progression was observed through imaging, patients initially assigned to the placebo group were allowed to switch to vorasidenib treatment.

Among patients diagnosed with Grade II gliomas harboring IDH mutations, vorasidenib demonstrated a notable enhancement in progression-free survival, with a median of 27.7 months compared to 11.1 months for those receiving a placebo. Additionally, vorasidenib exhibited a prolonged interval until the next treatment, which has not yet been reached, in contrast to 17.4 months for the placebo group. The administration of vorasidenib was well-tolerated, and its safety profile was manageable, as similar side effects were reported in both the placebo and treatment cohorts.

While the treatment group experienced adverse events such as fatigue, headache, diarrhea, nausea, COVID-19, and reversible liver transaminase elevations, the majority of these events were manageable and resolved with appropriate medical care. Among these events, the most frequent grade ≥ 3 adverse event was an increase in the liver enzyme alanine aminotransferase, which occurred in 9.6% of patients receiving vorasidenib.

KOL insights

“This study highlights the significant benefits of vorasidenib in minimizing the disabling long-term effects of current therapies for low-grade gliomas, particularly in younger patients, and has the potential to revolutionize care for this disease” –Expert Opinion.


The presence of an IDH mutation serves as a robust prognostic biomarker in glioma patients, indicating a favorable outcome regardless of age or grade. Approximately 80% of low-grade gliomas exhibit an IDH mutation. While IDH mutations are commonly found in Grade II gliomas, they are infrequent in various WHO grade I gliomas, such as gangliogliomas, subependymal giant cell tumors, pilocytic astrocytomas, ependymomas, and pleomorphic xanthoastrocytoma.

The field of low-grade glioma treatment has seen little progress for many years. Typically, patients with low-grade glioma undergo a "watch and wait" approach, and if the tumor shows signs of growth or progression, they must resort to more aggressive treatments such as surgery, radiation, and chemotherapy. This poses a challenge, particularly for young adult patients, as these treatments often come with significant toxicities. The analysis findings demonstrated that vorasidenib had a notable positive impact on progression-free survival as assessed by BIRC while maintaining an acceptable safety profile. This discovery presents an opportunity to transform the treatment approach for patients with IDH mutant low-grade glioma by potentially providing the first targeted therapy. Moreover, this therapy has the potential to delay the need for radiation therapy, which is particularly beneficial for the younger population affected by IDH mutant tumors