Targeting IDH mutations in Cancer

Somatic mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) arise in roughly 6–10% of patients with acute myeloid leukemia (AML). These mutations interfere with epigenetic control of gene expression, which prevents hematopoietic cell maturation. Ivosidenib (IVO; AG-120) is an oral, potent, targeted inhibitor of mutant IDH1(mIDH1)and is FDA-approved for the treatment of patients with mIDH1relapsed/refractory, patients with mIDH1 newly diagnosed AML who are ≥ 75 years of age or have comorbidities that preclude intensive induction chemotherapy. Currently, IVO is being investigated in combination with azacytidine (AZA) in adult participants with previously untreated mIDH1AMLin the actively enrolling phase 3 AGILE study (NCT03173248). To support this ongoing effort, studies were undertaken to explore the IVO+ AZA combination in a mIDH1AML patient-derived xenograft (PDX)model in vivo. Additionally, ongoing preclinical studies have been underway to examine the timing of IVO+ AZA treatment with respect to disease burden control and durability in mice inoculated with a disseminated mIDH1AML PDX model; both as an up-front treatment as well as in a maintenance therapy setting following either venetoclax (VEN) + AZA, or VEN + AZA + IVO. Initial findings from these murine AML PDX studies support the reported clinical observation that IVO + AZA combination treatment is superior at controlling mIDH1AML disease burden compared with either agent alone. Together, these data will enhance our understanding of how to best combine the use of these agents to achieve long term disease control. 3 Key Takeaways: • Ivosidenib is an FDA-approved targeted inhibitor of mIDH1that acts to promote hematopoietic cell maturation in AML • Murine studies indicate that IVO+ AZA combination treatment is superior at controlling mIDH1AML disease burden compared withIVO or AZA alone • IVO+ AZA is being investigated in participants with untreated mIDH1AMLin the phase 3 AGILE study