The oral IDH1/2 inhibitor vorasidenib significantly improved progression-free survival in patients with grade 2 gliomas expressing IDH1/2 mutations in the phase III INDIGO trial. These results, which were reported by lead author Ingo K. Mellinghoff, MD, FACP, of Memorial Sloan Kettering Cancer Center, New York, at the 2023 ASCO Annual Meeting,¹ and published simultaneouslay in The New England Journal of Medicine,² represent a major advance in treating this disease.

Ingo K. Mellinghoff, MD, FACP

“INDIGO is the first prospective, randomized phase III study of a targeted therapy in grade 2 IDH1/2-mutated glioma. Treatment with vorasidenib showed a statistically significant 61% reduction in the risk of tumor progression or death and significantly delayed the need for more toxic therapy when compared with placebo. The side effects of the drug were manageable,” said Dr. Mellinghoff.

“This is clinically meaningful because patients diagnosed with grade 2 gliomas with IDH mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma, where chemotherapy and radiation therapy are being delayed, and could bring the first new targeted therapy for low-grade glioma,” he told listeners.

Grade 2 gliomas in adults are slowly progressive, malignant brain tumors with a poor long-term prognosis. The current standard of care is surgery, followed by radiation therapy and chemotherapy (which are not curative and have been associated with short- and long-term toxicities), or close clinical and imaging-based surveillance following a “watch-and-wait” approach.

Mutations in IDH1/2 occur in nearly all grade 2 gliomas in adults and are a disease-defining characteristic. Vorasidenib is an oral dual inhibitor of mutant IDH1/2 enzymes specifically designed to be brain-penetrant.

Study Details

INDIGO is a global phase III, double-blind, randomized, crossover study that enrolled 331 patients at 77 centers across 10 countries. Participants were those with grade 2 IDH1/2-mutant diffuse glioma (per World Health Organization 2016 guidance) who had received surgery as their only prior treatment and were not in need of immediate chemotherapy or radiation therapy. Most recent surgery was 1 to 5 years from randomization. The primary endpoint was progression-free survival based on blinded independent imaging review. Time to next anticancer intervention was a key secondary endpoint. Stratification factors were 1p19q status and baseline tumor size. Patients were randomly assigned 1:1 to receive vorasidenib at 40 mg/d or placebo in 28-day cycles. Subjects randomly assigned to placebo were offered the option to cross over to receive vorasidenib upon centrally confirmed imaging-based disease progression.

Eligibility criteria were age 12 or older (at least 88 lb); Karnofsky Performance Score (KPS) of at least 80; residual or recurrent grade 2 oligodendroglioma or astrocytoma with IDH1/2 mutation, oligodendroglioma, or astrocytoma; and nonenhancing disease. At baseline, median patient age was 40.4 years, with a KPS of 100 in approximately half of all patients. Oligodendroglioma was present in 172 patients and astrocytoma, in 159 patients.

Key Results and Safety Profile

At a preplanned interim analysis, vorasidenib demonstrated a significant improvement in progression-free survival per blinded independent imaging review, reducing the risk of disease progression or death by 61% compared with placebo, which was statistically significant (hazard ratio [HR] = 0.39; 95% confidence interval [HR] = 0.27–0.56; P = .000000067). Median progression-free survival was 27.7 months with vorasidenib vs 11.1 months with placebo. Vorasidenib significantly delayed the time to next intervention by 74%, again a difference that was highly statistically significant (HR = 0.39; 95% CI = 0.27–0.56; P = .000000019). The probability of not receiving a next treatment intervention by 24 months was 83 % in the vorasidenib group and 27 % in the placebo group.

All-grade adverse events occurring in 20% or more of patients on vorasidenib treatment included elevated alanine aminotransferase (ALT) levels, COVID-19 infection, fatigue, elevated aspartate aminotransferase, headache, diarrhea, and nausea. Grade 3 or higher elevated ALT levels occurred in 9.6% of vorasidenib-treated patients vs 0% of placebo patients. Adverse events leading to dose reductions were 10.8% in the vorasidenib arm compared with 3.1.% in the placebo group. Adverse events leading to dose interruptions occurred for approximately one-quarter of patients in both arms.

Additional Commentary

ASCO expert Glenn J. Lesser, MD, FACP, a neuro-oncologist at Wake Forest Baptist Health, Winston-Salem, North Carolina, commented on grade 2 gliomas in general and the INDIGO trial findings.

Glenn J. Lesser, MD, FACP

“About 40,000 patients per year in the United States develop grade 2 gliomas. The known natural history is generally favorable. Over the past decade or so, grade 2 gliomas have been linked to the presence of IDH mutations in the tumor. When therapy is needed, it involves chemotherapy and radiation. There is great concern about long-term effects, particularly neurocognitive effects. Combine this with the fact that these patients are typically in their most productive years and suffer often disabling side effects of therapy,” he explained.

Dr. Lesser continued: “INDIGO is a well-designed study to determine whether we could delay chemotherapy and radiation therapy. The results are highly statistically significant and, more important, clinically significant. With vorasidenib, we can potentially delay the use of radiation and chemotherapy for years, and maybe many years, in a group of patients who survive a long time.”

Julie R. Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO, pointed out that vorasidenib is not yet approved by the U.S. Food and Drug Administration. “It has been granted Fast Track designation status with the FDA in March, so hopefully it will be accessible for these patients soon,” she noted. 

DISCLOSURE: The study was funded by Servier. Dr. Mellinghoff has received honoraria from Roche, Prelude Therapeutics, Black Diamond Therapeutics, and Hartford Hospital; has served as a consultant or advisor to Agios, Debiopharm Group, Black Diamond Therapeutics, Voyager Therapeutics, Cardinal Health, Divide and Conquer, Novartis Pharma AG, Roche Ltd, Servier, and the Global Coalition for Active Research; has received research funding from General Electric, Amgen, Eli Lilly, Kazia Therapeutics, and Servier Pharmaceuticals; and has received reimbursement for travel, accommodations, expenses from Voyager, AstraZeneca, Roche, Puma Biotechnology, and Agios. Dr. Lesser has received honoraria from SDP Oncology; has served as a consultant or advisor to Cancer Expert Now, Agios, IN8bio, and Ono Pharmaceuticals; and has received research funding from Novocure, Oblagto, Denovo Biopharma, GCAR, Incyte, and CNS Pharmaceuticals. Dr. Gralow reported no conflicts of interest.

REFERENCE

1. 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. 2023 ASCO Annual Meeting. Abstract LBA1. Presented June 4, 2023.

2. Mellinghoff IK, Van Den Bent MJ, Blumenthal DT, et al: Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. June 4, 2023 (early release online).