INDIGO
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma
Clinical Question
In patients with residual or recurrent grade 2 IDH-mutant glioma who have undergone surgery only, does vorasidenib (a dual IDH1/IDH2 inhibitor) improve progression-free survival compared with placebo during the watch-and-wait period?
Study Overview
Objective
To determine whether vorasidenib, an oral dual IDH1/IDH2 inhibitor, improves progression-free survival compared with placebo in patients with residual or recurrent grade 2 IDH-mutant glioma after surgery alone
Study Summary
- Median PFS: 27.7 months (vorasidenib) vs 11.1 months (placebo); HR 0.39 (95% CI 0.27-0.56), P<0.001
- Time to next intervention: HR 0.26 (95% CI 0.15-0.43), P<0.001
- Imaging-based progression: 28.0% (vorasidenib) vs 54.0% (placebo)
- No deaths in either group at median follow-up of 14.2 months
- Grade >=3 AEs: 22.8% (vorasidenib) vs 13.5% (placebo)
- Elevated ALT grade >=3: 9.6% (vorasidenib) vs 0% (placebo)
- Crossover from placebo to vorasidenib permitted after confirmed progression
- First targeted therapy for IDH-mutant glioma to show PFS benefit in a phase 3 trial
Intervention
Vorasidenib 40 mg orally once daily in continuous 28-day cycles vs matched placebo; treatment continued until disease progression, unacceptable toxicity, or indication for other anticancer therapy; crossover permitted
Patients per Arm
Vorasidenib: 168; Placebo: 163
Bottom Line
Vorasidenib significantly improved median progression-free survival from 11.1 to 27.7 months (HR 0.39, P<0.001) and delayed the time to next intervention (HR 0.26, P<0.001) in grade 2 IDH-mutant glioma patients on watch-and-wait after surgery. This was the first phase 3 trial to demonstrate efficacy of a targeted IDH inhibitor in glioma, offering a well-tolerated oral therapy that can defer radiation and chemotherapy.
Major Points
- INDIGO was the first randomized, double-blind, placebo-controlled, phase 3 trial of a targeted IDH inhibitor in glioma, enrolling 331 patients at 77 centers across 10 countries.
- The trial uniquely targeted the watch-and-wait population — patients with residual/recurrent grade 2 IDH-mutant glioma after surgery who had not yet received radiation or chemotherapy.
- The primary endpoint was met with a dramatic 61% reduction in the risk of progression or death: median PFS 27.7 vs 11.1 months (HR 0.39; 95% CI 0.27-0.56; P<0.001).
- The key secondary endpoint — time to next intervention (RT, chemo, or surgery) — was even more striking: HR 0.26 (95% CI 0.15-0.43; P<0.001), meaning vorasidenib substantially delayed the need for more toxic therapies.
- At the data cutoff, imaging-based progression occurred in only 28.0% of the vorasidenib group vs 54.0% of the placebo group. No deaths occurred in either group at median follow-up of 14.2 months.
- The safety profile was manageable: grade >=3 AEs in 22.8% (vorasidenib) vs 13.5% (placebo). The main toxicity was elevated ALT (grade >=3 in 9.6% vs 0%), requiring liver function monitoring.
- The trial was unblinded early at the second prespecified interim analysis based on overwhelming efficacy, and patients in the placebo group were allowed to cross over to vorasidenib.
- INDIGO represents a paradigm shift in low-grade glioma management — offering a targeted, oral therapy during the watch-and-wait period that can delay or defer the neurotoxicity associated with radiation and chemotherapy.
Design
Study Type: Randomized, double-blind, placebo-controlled, multicenter, international, phase 3 trial
Randomization: 1
Blinding: Double-blind (patients, investigators, sponsor); blinded independent review committee for imaging assessment
Enrollment Period: January 2020 - February 2022
Follow-up Duration: Median 14.2 months (data cutoff September 6, 2022)
Centers: 77
Countries: 10 countries
Sample Size: 331
Analysis: Intention-to-treat; stratified log-rank test; stratified Cox proportional-hazards model; group-sequential design with 3 prespecified interim analyses; fixed-sequence testing for primary and key secondary endpoints
Inclusion Criteria
- Age >=12 years
- Residual or recurrent histologically confirmed grade 2 oligodendroglioma or astrocytoma (WHO 2016 criteria)
- Centrally confirmed IDH1 (R132H, R132C, R132G, R132S, or R132L) or IDH2 (R172K, R172M, R172W, R172S, or R172G) mutation
- Karnofsky performance-status score >=80
- At least one previous surgery, most recent 1-5 years before randomization
- No other prior anticancer treatment for glioma (no prior RT or chemotherapy)
- No use of glucocorticoids for signs/symptoms of glioma
- Appropriate candidate for a watch-and-wait approach
- Measurable nonenhancing disease (>=1 target lesion measuring >=1 cm x >=1 cm on MRI, centrally assessed)
- Adequate hepatic and renal function
Exclusion Criteria
- Uncontrolled seizures
- Brain-stem involvement
- Clinically relevant functional or neurocognitive deficits caused by the tumor
- High-risk features assessed by investigator
- QTc interval >=450 msec (Fridericia's formula)
- More than minimal, nodular, or measurable contrast enhancement on MRI
Arms
| Field | Experimental | Control |
|---|---|---|
| Intervention | Vorasidenib 40 mg orally once daily in continuous 28-day cycles until disease progression, unacceptable toxicity, or need for other anticancer therapy | Matched placebo orally once daily in continuous 28-day cycles; crossover to vorasidenib permitted after confirmed imaging-based progression |
| Duration |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| PFS (blinded independent review, RANO-LGG): median 27.7 vs 11.1 months; HR 0.39 (95% CI 0.27-0.56); P<0.001 | Primary | 0.39 | P<0.001 | ||
| Time to next intervention: HR 0.26 (95% CI 0.15-0.43); P<0.001 | Secondary | 0.26 | P<0.001 | ||
| Imaging-based progression: 47/168 (28.0%) vs 88/163 (54.0%) | Secondary | ||||
| No deaths in either group | Secondary | ||||
| Best overall response by blinded independent review reported in Table S4; tumor-volume growth rate data not yet available | Secondary | ||||
| Grade >=3 AEs: 22.8% vs 13.5% | Secondary | ||||
| ALT elevation grade >=3: 9.6% vs 0%; AST elevation grade >=3: 4.2% vs 0% | Secondary | ||||
| Treatment discontinuation due to AE: 3.6% (vorasidenib) vs 1.2% (placebo) | Secondary | ||||
| Any AE | Adverse | 152 (93.3%) | 158 (94.6%) | ||
| Grade >=3 AE (any) | Adverse | 22 (13.5%) | 38 (22.8%) | ||
| Increased ALT (any grade) | Adverse | 24 (14.7%) | 65 (38.9%) | ||
| Increased ALT grade >=3 | Adverse | 0 | 16 (9.6%) | ||
| Increased AST (any grade) | Adverse | 13 (8.0%) | 48 (28.7%) | ||
| Increased AST grade >=3 | Adverse | 0 | 7 (4.2%) | ||
| Increased GGT grade >=3 | Adverse | 2 (1.2%) | 5 (3.0%) | ||
| Seizure (any grade) | Adverse | 19 (11.7%) | 23 (13.8%) | ||
| Seizure grade >=3 | Adverse | 4 (2.5%) | 7 (4.2%) | ||
| Serious AE related to treatment | Adverse | 0 | 3 (1.8%) | ||
| AE leading to discontinuation | Adverse | 2 (1.2%) | 6 (3.6%) | ||
| AE leading to dose reduction | Adverse | 5 (3.1%) | 18 (10.8%) | ||
| Safety analysis set N | Adverse | 163 | 167 | ||
Funding
Servier (acquired Agios Pharmaceuticals oncology business, the original sponsor)
Based on: INDIGO (New England Journal of Medicine, 2023)
Authors: Ingo K. Mellinghoff, Martin J. van den Bent, Deborah T. Blumenthal, ..., for the INDIGO Trial Investigators
Citation: N Engl J Med 2023;389:589-601
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