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IDH Inhibitors for Low Grade Glioma

IDH Inhibitors for Low Grade Glioma 

  • Low-grade gliomas (LGG), ie. astrocytomas and oligodendrogliomas are a group of primary brain tumors that arise from supporting glial cells
  • Oligodendrogliomas have a better prognosis than astrocytomas
  • % of LGG harbor IDH1 or IDH2 mutations, 95% off IDH mutations are found in the IDH1 isoform
  • Small molecule Inhibitors targeting IDH mutations include:

         -Ivosidenib: IDH1 inhibitor

         -Vorasidenib: IDH1/2 inhibitor (1) 

 

 

  • Vorasidenib significantly improved progression-free survival in patients with grade 2 IDH-mutant glioma (median progression-free survival was 27.7 months in the vorasidenib group vs. 11.1 months in the placebo group; double-blind, randomized phase 3 trial; n=331).

    Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo (2)

  • Ivosidenib 500 mg once per day was administrated to 2 cohorts (enhancing/non enhancing gliomas) and was associated with a favorable safety profile and prolonged disease control (median progression-free survival times were 13.6 months and 1.4 months for the non enhancing and enhancing glioma cohorts, respectively, across all doses; open-label, phase I trial; n=54) (3)
  • Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive non enhancing mutant IDH low grade glioma (The median progression-free survival was 36.8 months for non enhancing glioma and 3.6 months for enhancing glioma; open-label phase I trial; n=52) (4)

References:

1-    Youssef G. et. al. (2020). Curr Neurol Neurosci Rep, 20(7):21

2-    Mellinghoff, I. K. et. al. (2023). The New England journal of medicine

3-    Mellinghoff, I. K. et. al. (2020). Journal of clinical oncology, 38(29), 3398

4-    Mellinghoff, I. K. et. al. (2021). Clinical cancer research, 27(16), 4491