Abstract 6417: LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML)
Authors: Salama Vivian , Brooks Nathan , Skwarska Anna , Kays Lisa , Milligan Paul , Newell Katherine , Roth Kenneth , Geeganage Sandaruwan , Gilmour Raymond , Chan Steven M. , Sarry Jean-Emmanuel , Sabatier Mary , DiNardo Courtney , Konopleva Marina 
Published: September 2020

Abstract
Acute myeloid leukemia is associated with the abnormal proliferation of myeloid progenitor cells unable to differentiate. Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 occur in 10% of newly diagnosed AML patients. IDH1 mutations cause intracellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG), which results in a hyper-methylation phenotype and a block in differentiation. Inhibitors of IDH1 mutant enzyme reduce levels of 2-HG, which relieves the differentiation block allowing AML cells to achieve terminal maturation. Recently, Ivosidenib, an IDH1 inhibitor, has been approved for use in AML patients. However, based on clinical findings, a fraction of the IDH1 mutant AML patients treated with Ivosidenib are primary refractory or relapse while on therapy. This raises the need for development of more potent inhibitors targeting IDH1. Lilly Research Laboratories have developed a potent covalent inhibitor of mutant IDH1, LY3410738 that modifies a single cysteine (Cys269) in an allosteric binding pocket and rapidly inactivates the enzyme, selectively inhibiting 2-HG production without affecting alpha-ketoglutarate (a-KG) levels. Here, we have assessed the activity of LY3410738 in IDH1 mutated patient-derived AML models and AML cell lines engineered to express wild-type IDH1 or mutant IDH1R132H. In vitro, LY3410738 displayed greater potency for inhibition of 2-HG production and differentiation of the IDH1 mutant cells compared to AG-120. Similarly, in vivo, we observed sustained 2-HG inhibition leading to a more robust and durable efficacy for LY3410738 with respect to AG-120. We next evaluated the combination activity of LY3410738 with Cytarabine and Azacitidine or the FLT3 inhibitor Midostaurin, the latter in FLT3-mutated AML. Combining LY3410738 with the chemotherapeutics resulted in increased efficacy, exhibiting a potent anti-leukemic effect, reduction of 2-HG level, and enhanced differentiation of the leukemic blasts in the mice. In addition, since IDH1 mutant AML cells have been shown to strongly depend on the anti-apoptotic Bcl-2 for the survival, we also combined LY3410738 with FDA approved Bcl-2 inhibitor, venetoclax. In vitro, isogenic cells with IDH1R132H mutation were more sensitive to the combination than wild-type IDH1-expressing cells.
Importantly, the combination of LY3410738 with Venetoclax was also efficacious in an AML xenograft model derived from a patient refractory to AG-120. In conclusion, LY3410738 exhibits enhanced efficacy in IDH1 mutant AML PDX models in combination with Cytarabine, Azacitidine, Midostaurin and Venetoclax and demonstrates improved potency and durability compared to Ivosidenib.
Citation Format: Vivian Salama, Nathan Brooks, Anna Skwarska, Lisa Kays, Paul Milligan, Katherine Newell, Kenneth Roth, Sandaruwan Geeganage, Raymond Gilmour, Steven M. Chan, Jean-Emmanuel Sarry, Mary Sabatier, Courtney DiNardo, Marina Konopleva. LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6417.