Vorasidenib Approved for Grade 2 Astrocytoma or Oligodendroglioma With a Susceptible IDH1 or IDH2 Mutation
Expert Perspectives · Lyn Brook · 2024-08-09
The FDA has granted approval to vorasidenib (Voranigo®, Servier Pharmaceuticals LLC), an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, for adult and pediatric patients 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.
Why it matters: “As an incurable disease that typically affects young adults, a diagnosis of IDH-mutant grade 2 glioma—either astrocytoma or oligodendroglioma—is both life-altering and life-limiting,” wrote Oncology Editorial Board member Jethro Hu, MD, a Neuro-Oncologist at Cedars-Sinai Cancer and an Associate Professor in the Departments of Medicine, Neurology, and Neurosurgery at Cedars-Sinai Medical Center, regarding the approval and the INDIGO trial (NCT04164901), on which approval was based. “Historically, management options for these patients have been restricted to implementing radiation and cytotoxic chemotherapy regimens designed and better studied for higher-grade tumors or taking a watch-and-wait approach in an effort to delay treatment-related adverse events. The recent FDA approval of the oral brain-penetrant IDH1/IDH2 inhibitor vorasidenib for IDH-mutant grade 2 glioma—based largely on the impressive results seen in the phase 3 INDIGO trial—means we now have another important tool in our therapeutic armamentarium for this challenging disease.”
What they studied: Efficacy was measured in the phase 3, double-blind, placebo-controlled trial, in which 332 patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery were enrolled. Patients were randomized 1:1 to receive either 40 mg of vorasidenib orally once daily, or placebo orally once daily, until disease progression or unacceptable toxicity. The Life Technologies Corporation Oncomine Dx Target Test was used to determine IDH1 or IDH2 mutation status. Those who were randomized to receive placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Patients were excluded if they had received prior anticancer treatment, including chemotherapy and radiation therapy.
The primary end point measured was progression-free survival using a Blinded Independent Review Committee per modified Response Assessment in Neuro-Oncology for Low-Grade Glioma (RANO-LGG) criteria. A key secondary end point measured was time to next intervention.
What they found: Progression-free survival saw a hazard ratio of 0.39, and the median time to next intervention was not reached for the vorasidenib arm compared with the placebo arm at a median of 17.8 months.
Adverse events: The most common adverse events experienced by ≥15% of patients receiving vorasidenib were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizure. The most common grade 3 or 4 laboratory abnormalities experienced in >2% of patients were increased alanine aminotransferase, increased aspartate aminotransferase, gamma-glutamyl transferase (GGT) increased, and decreased neutrophils.
Conclusion: “The FDA approval of vorasidenib represents the culmination of years of research, beginning with the unexpected identification of IDH mutations in glioma, elucidating the mechanisms by which these mutations alter metabolism and induce tumorigenesis, and concluding with a randomized phase 3 trial that demonstrated such a clear improvement in progression-free survival that the trial was unblinded after a pre-planned interim analysis in order to allow patients on the placebo arm to receive active drug,” concluded Dr. Hu. “It is worth noting that the INDIGO trial excluded patients with high-risk features, such as functional deficits or nodular contrast enhancement on magnetic resonance imaging (MRI). Additionally, effects on health-related quality of life and cognition are not yet available, and the impact of treatment on overall survival is not yet known. It also remains to be determined whether and how vorasidenib treatment should be combined with other therapeutic modalities. Yet, while these and many other questions remain, the FDA approval of vorasidenib is an important step in the right direction.”
Instructions: The recommended dosage of vorasidenib for adults 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; and for patients weighing <40 kg, the recommended dose is 20 mg orally once daily.