Clinical trialPhase 3Brain tumours

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma

N Engl J Med · 2023331 patients (168 vorasidenib, 163 placebo)

Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. N Engl J Med. 2023. 389:589-601

Study type: Clinical trial
Study name: INDIGO
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled international trial (1:1 randomisation); crossover from placebo to vorasidenib allowed after confirmed progression
Sample size: 331 patients (168 vorasidenib, 163 placebo)
Source: N Engl J Med · 2023
Trial registration: NCT04164901

In plain words

Many low-grade gliomas (grade 2) have a change called an IDH mutation. Vorasidenib is a daily tablet that blocks the mutated IDH enzyme and reaches the brain. In this study, patients who did not yet need radiotherapy or chemotherapy straight away after surgery stayed free of tumour growth on average more than twice as long with vorasidenib, and their need for radiotherapy or chemotherapy was delayed; this means being spared for longer from the possible effects of these treatments on memory and thinking. The most important side effect is a rise in liver enzymes, which is watched with regular blood tests.

Key results

27.7 vs 11.1 months

Median progression-free survival

HR for progression or death 0.39 (95% CI 0.27–0.56); P<0.001; median follow-up 14.2 months

HR 0.26

Time to next intervention

95% CI 0.15–0.43; P<0.001. According to the FDA: median not reached in the vorasidenib group vs 17.8 months with placebo

22.8% vs 13.5%

Grade 3 or higher adverse events

Grade ≥3 ALT increase: 9.6% vs 0%

Dose and schedule cards

Vorasidenib (INDIGO)

Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation, after surgery (biopsy, subtotal or gross total resection), age 12 years or older; in patients in whom radiotherapy and chemotherapy can be deferredOn the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Drug	Dose	Route	Schedule
Vorasidenib	40 mg once daily (children aged 12 years and older weighing less than 40 kg: 20 mg)	Oral	Continuously, with or without food

Cycle length: Continuous (28-day cycles in the trial)
Duration: Until progression or unacceptable toxicity

Hepatotoxicity: liver tests before starting, every 2 weeks for the first 2 months, then monthly for up to 2 years; depending on severity, withhold, reduce the dose or discontinue permanently. Dose reductions (adults and patients weighing 40 kg or more): 20 mg, then 10 mg daily; discontinue permanently if 10 mg is not tolerated. Avoid concomitant strong and moderate CYP1A2 inhibitors, moderate CYP1A2 inducers and smoking; non-hormonal contraception is required. Swallow tablets whole; take a missed dose only if no more than 6 hours have passed. Grade 3 or higher ALT elevation occurred in 9.6% of patients.

On the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Vorasidenib

Vorasidenib 40 mg orally once daily, in 28-day cycles, until disease progression or unacceptable toxicity.

2Placebo

Matching oral placebo once daily in 28-day cycles; crossover to vorasidenib was allowed after confirmed imaging progression.

Source of the regimen details: The vorasidenib dose (40 mg once daily in 28-day cycles) is stated in the published abstract of the NEJM 2023 paper and was confirmed by the FDA approval announcement (6 August 2024); inclusion criteria from the author manuscript in PMC (PMC11445763).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 12 years and older with residual or recurrent grade 2 oligodendroglioma or astrocytoma (WHO 2016) with a centrally confirmed IDH1 or IDH2 mutation; KPS ≥80; at least one previous surgery (the most recent 1 to 5 years before randomisation); no other anticancer treatment (no previous radiotherapy or chemotherapy); no immediate need for chemotherapy or radiotherapy and no need for corticosteroids; measurable non-enhancing disease.

Endpoints

Primary endpoint: imaging-based progression-free survival assessed by a blinded independent committee.

Key secondary endpoint: time to next anticancer intervention (such as radiotherapy or chemotherapy). Safety was also assessed.

Safety and side effects

Grade 3 or higher adverse events occurred in 22.8% of patients in the vorasidenib group and 13.5% in the placebo group. The most common severe adverse event was grade ≥3 increased alanine aminotransferase (ALT) (9.6% versus 0%); regular monitoring of liver tests is therefore needed. According to the FDA announcement, the most common adverse events (≥15%) were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhoea, nausea and seizures.

Clinical significance and place in guidelines

On 6 August 2024 the FDA approved vorasidenib (Voranigo) for adults and children aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery (including biopsy, subtotal or gross total resection); it is the first systemic therapy approved for these patients. The recommended adult dose is 40 mg orally once daily. The drug is an option for delaying radiotherapy and chemotherapy in selected patients. (The EANO 2021 guideline was published before this trial and does not include it.)

Limitations

Short follow-up (median 14.2 months) at the time of publication; overall survival data were not yet mature and may be difficult to interpret because of crossover from the placebo group. Only patients without an immediate need for treatment and without contrast-enhancing tumour were enrolled; the results do not extend to grade 3 gliomas or to patients previously treated with radiotherapy/chemotherapy. Neurocognitive and quality-of-life outcomes were to be reported later.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.