The U.S. Food and Drug Administration (FDA) has approved vorasidenib (Voranigo), an isocitrate dehydrogenase-1 (IDH1) and -2 (IDH2) inhibitor, for adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, subtotal resection, or gross total resection. The August 6th approval is the first by the FDA of a systemic therapy for patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.
INDIGO
Efficacy was evaluated in 331 patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery enrolled in INDIGO (ClinicalTrials.gov identifier NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial. Patients were randomly assigned 1:1 to receive vorasidenib at 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. IDH1 or IDH2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.
Patients assigned to receive placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Patients who received prior anticancer treatment, including chemotherapy or radiation therapy, were excluded.
The major efficacy outcome measure was progression-free survival using a blinded independent review committee per modified Response Assessment in Neuro-Oncology for Low Grade Glioma criteria. An additional efficacy outcome measure was time to next intervention. The hazard ratio for progression-free survival was 0.39 (95% confidence interval [CI] = 0.27–0.56, P < .0001). The median time to next intervention was not reached for the vorasidenib arm and was 17.8 months for the placebo arm (hazard ratio [HR] = 0.26, 95% CI = 0.15–0.43, P < .0001).
Adverse reactions occurring in ≥ 15% of patients who received vorasidenib were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizure. The most common grade 3 or 4 laboratory abnormalities (occurring in > 2% of patients) were increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyl transferase, and decreased neutrophils.
The recommended vorasidenib dose in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity. The recommended vorasidenib dose in pediatric patients 12 years and older is based on body weight:
- For patients weighing ≥ 40 kg, the recommended dose is 40 mg orally once daily.
- For patients weighing < 40 kg, the recommended dose is 20 mg orally once daily.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, Switzerland’s Swissmedic, and Israel’s Ministry of Health. The application reviews are ongoing at the other regulatory agencies.
This review also used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review, Fast Track designation, Breakthrough Therapy designation, and Orphan Drug designation.
