Abstract IA24: IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit

Abstract Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers including cholangiocarcinoma. These hotspot gain-of-function mutations will lead to the IDH enzyme to aberrantly produce high levels of R-2-hydroxyglutarate (2-HG), which is thought to be the oncometabolite. 2-HG can competitively inhibit enzymes that regulate epigenetics, DNA repair, metabolism, and it can also modulate tumor immune microenvironment. IDH-1 mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA), and their frequency varies depending on the geographic location and underlying etiology. Many inhibitors targeting mutant IDH (mIDH) are under active clinical development. Results from the phase III ClarIDHy trial have demonstrated that ivosidenib-a first-in-class, oral, small-molecule inhibitor of mutant IDH1, was well tolerated and could improve progression-free survival and a favorable overall survival benefit versus placebo, leading to the regulatory approval of ivosidenib in mIDH1 cholangiocarcinoma. The author will discuss the rationale, current clinical development, unanswered questions including the mechanism of resistance, and the optimal combination strategies that can more effectively harness mIDH as a therapeutic target. Citation Format: Andrew X. Zhu. IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA24.