This marks the first FDA-approved systemic therapy for patients with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IHD1) or IDH2 mutation.
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Trial Name: Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
ClinicalTrials.gov ID: NCT04164901
Sponsor: Institut de Recherches Internationales Servier
Completion Date (Estimated): August 2027
The FDA approved vorasidenib (Voranigo; Servier Pharmaceuticals LLC) for adult and pediatric patients 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or IDH2 mutation. It is indicated for post-surgery use, such as after biopsy, sub-total resection, or gross total resection. This is the first FDA-approved systemic therapy for patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.1
Vorasidenib is a selective oral highly brain-penetrant dual inhibitor of the mutant IDH1 and IDH2 enzymes. IDH mutation impacts approximately 20% of patients who are diagnosed with primary malignant brain tumors with adult-type diffuse gliomas, and this includes 100% of grades 2 and 3 adult-type diffuse gliomas. In February 2024, vorasidenib was granted priority review following the acceptance of the new drug application.2
"Patients living with grade 2 IDH-mutant gliomas have long faced the harsh reality of an incurable disease with very limited post-surgery treatment options," said Ralph DeVitto, president & CEO of the American Brain Tumor Association, in a news release. "The FDA approval of [vorasidenib] marks a monumental breakthrough in glioma treatment, offering renewed hope for patients and their families living with this relentless disease."3
The approval comes after positive efficacy and safety results from the randomized, multicenter, double-blind, placebo-controlled phase 3 clinical trial INDIGO (NCT04164901). A total of 331 patients with grade 2 astrocytoma or oligodendroglioma were randomly assigned to receive either 40 mg of oral vorasidenib once per day (n = 168) or a matching placebo (n = 163) until disease progression or unacceptable toxicity. The recommended vorasidenib dose in adult patients is 40 mg once per day, and for pediatric patients, the recommended doses are 40 mg once per day for those who weigh 40 kg or more and 20 mg once per day for those who weigh less than 40 kg.1,4,5
Those who were randomly assigned to receive placebo were able to cross over to vorasidenib following documented radiographic disease progression. Additionally, patients were excluded from the trial if they received prior anti-cancer treatment, such as chemotherapy or radiation therapy.1,4
The major efficacy outcome measure was progression-free survival (PFS), and an additional efficacy outcome measure was time to next intervention. At a median follow-up of 14.2 months, approximately 68.3% of patients (n = 226) were continuing to receive either vorasidenib or placebo. According to the findings, PFS was significantly improved in the vorasidenib group (median: 27.7 months) compared with the placebo group (median: 11.1 months; Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27-0.56; 1-sided P < .001). Additionally, time to next intervention was considered statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P < .001); however, it was not achieved in the vorasidenib group but was 17.8 months in the placebo group. The investigators also observed a reduction in tumor volumes by a mean of 2.5% (TGR of –2.5%; 95% CI: -4.7% to -0.2%) every 6 months in the vorasidenib group, whereas tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1% to 16.8%) every 6 months in the placebo group.1-3,5
The most common adverse events (≥15%) reported by patients were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizure. Additionally, the most common grade 3 or 4 laboratory abnormalities (>2%) were increases in alanine aminotransferase, aspartate aminotransferase, and GGT, as well as decreased neutrophils.1
"Today's approval of [vorasidenib] is an enormous leap forward in cancer care, and a defining moment for people living with Grade 2 IDH-mutant glioma," said Arjun H. Prasad, chief commercial officer at Servier Pharmaceuticals, in the news release. "[Vorasidenib], which is the first breakthrough in this specific disease area in nearly 25 years, offers patients unprecedented improvement in PFS. We are proud to deliver this first-of-its-kind therapy to patients in need, and we remain committed to bringing innovative targeted therapies to people with cancer."3
