Goodman & Gilman's: Annual FDA Approvals

Tibsovo^47,#

Isocitrate dehydrogenase-1 (IDH1) inhibitor⁴⁶

IDH1 mutated myeloid leukemia^†

Ivosidenib is the first-in-class isocitrate dehydrogenase-1 (IDH1) inhibitor. It is approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation (i.e., R132C, R132H, R132G, R132S and R132L)⁸⁹ as detected by the Abbott RealTime^TM IDH1 Assay (Abbott Laboratories).³⁴ Ivosidenib has been designated as an orphan drug for AML since 2015, for cholangiocarcinoma since 2017, and for glioma since 2018.²¹ Per the approved labeling, susceptible IDH1 mutations are those that result in a new ability of the enzyme to catalyze the reduction of alpha-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG).^90-93 2HG is an inhibitor of αKG-dependent dioxygenases, which include several histone demethylases.^91-93 2HG accumulation in IDH1-expressing cancer cells promotes hypermethylation of histones, suppression of cell-differentiation genes, and disruption of hematopoietic cell differentiation.^91,93 Administration of ivosidenib is demonstrated to reduce 2-HG levels in plasma and bone marrow.⁹³ By reducing the abnormal production of 2HG, ivosidenib is thought to reduce the inhibition of histone demethylases and promote normalization of cell methylation conditions.^91,93 In patients with AML, administration of ivosidenib reduces blast counts, increases mature myeloid cells, and leads to cancer regression.^47,91

The adverse effects of particular importance associated with ivosidenib therapy include differentiation syndrome (10%), leukocytosis (10%), prolonged QTc interval (7%), and Guillain-Barré syndrome (<1%).⁴⁷ At least one case of progressive multifocal leukoencephalopathy has been reported.⁴⁷ Assessments of blood counts, blood chemistries, blood creatine phosphokinase, and electrocardiograms are necessary to gauge the clinical response to ivosidenib and guide toxicity-related dose modifications (refer to the product labeling for details).⁴⁷ Ivosidenib is given orally at a dose of 500 mg once daily until disease progression or unacceptable toxicity.⁸⁹ Treatment for 6 months may be required for a clinical response.⁴⁷ Ivosidenib has a half-life of 93 hours and reaches steady-state within 14 days of therapy initiation.⁸⁹ It is primarily metabolized by CYP3A4 with elimination mainly in the feces.⁴⁷ Ivosidenib is an inducer of CYP3A4 and may induce CYPs 2B6, 2C8, and 2C9.⁴⁷ Dose modifications are necessary if ivosidenib must be co-administered with a strong CYP3A4 inhibitor.⁴⁷ Ivosidenib also is a substrate for and inhibitor of P-glycoprotein and an inhibitor of OAT3.⁴⁷ The chemical structure of ivosidenib is shown in Figure P1-4.

FDA approval of ivosidenib for AML was made on the basis of results from an open-label, single-arm, multicenter clinical trial of 174 adult patients with relapsed or refractory AML (NCT02074839).^47,94 Complete remission was achieved in 43 patients (24.7%) with a median duration just over 10 months.⁴⁷ Complete remission or a complete remission with a partial hematologic recovery that lasted for a median of just over 8 months was achieved by 32.8% of patients.⁴⁷

• Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules

• eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals