Abstract A071: AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor, promotes morphologic changes and upregulates liver-specific genes in IDH1 mutant cholangiocarcinoma (2018)

Abstract Background: Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been reported in ~25% of patients with intrahepatic cholangiocarcinoma (CC). The mutant IDH1 (mIDH1) enzyme has a gain-of-function activity, catalyzing the reduction of alpha-ketoglutarate to D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG leads to epigenetic dysregulation, and potential silencing of genes that control cellular differentiation. In a preclinical model of liver development, IDH1 mutation resulted in HNF4A silencing and impaired hepatocyte differentiation. AG-120 (ivosidenib) is a first-in-class, oral, selective inhibitor of mIDH1 that has been shown to reduce 2-HG levels in plasma and tumor tissue in preclinical and clinical studies, and to induce differentiation of leukemic blasts in patients with acute myeloid leukemia. In solid tumors, the consequences of IDH1 mutations and the effects of inhibition are less understood. In AG120-C-002 (ClinicalTrials.gov NCT02073994), a phase 1 clinical trial in mIDH1 advanced solid tumors, 73 patients with CC were treated with AG-120 at doses ranging from 100 mg twice daily to 1200 mg once daily. Among the phase 1 CC subjects who underwent on-study biopsies, we assessed morphologic and gene expression profile changes to understand the relationship between these parameters. Methods: Biopsy samples were collected from patients with CC enrolled in AG120-C-002 at screening, Cycle 3 Day 1, and in some cases Cycle 7 Day 1, disease progression, and end of treatment. Fourteen pre- and post-dose formalin-fixed paraffin-embedded (FFPE) tumor sample pairs were evaluable for morphology assessment (from 27 FFPE pre- and post-dose pairs collected), and 19 pre- and post-dose fresh frozen tumor sample pairs underwent gene expression profiling (from 38 pre- and post-dose pairs collected). Both morphology and gene expression data were assessed in eight patients to elucidate their relationship. Hematoxylin and eosin stained sections were evaluated for a cholangiocellular growth pattern and cytoplasmic alterations by two gastrointestinal pathologists from independent institutions. Gene expression profiles were generated by RNA sequencing to relate to morphologic changes. Results: Morphologic assessment of 14 pre- and post-dose sample pairs showed that upon 8-24 weeks of AG-120 treatment, a subset of CCs exhibited change in two phenotypes: (a) an increase of 20% or more in the cholangiocellular growth pattern (n=5), and (b) a reduction in the volume of cytoplasm (n=8). Changes in both phenotypes (a) and (b) were seen in five cases. RNA sequence profiling in samples with increased cholangiolar histology also showed a trend toward increased liver-specific gene expression. Conclusions: This is the first demonstration that AG-120 treatment may induce morphologic and molecular changes in a subset of mIDH1 CCs. Correlation of changes in morphology and gene expression with specific clinical outcomes will be described. Further studies, such as methylation changes, protein change by immunohistochemistry, and preclinical studies, are warranted to understand the biology of these morphologic and gene expression changes. Citation Format: Yuko Ishii, Carlie Sigel, Maeve A. Lowery, Lipika Goyal, Camelia Gliser, Liewen Jiang, Susan Pandya, Bin Wu, Sung Choe, Vikram Deshpande. AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor, promotes morphologic changes and upregulates liver-specific genes in IDH1 mutant cholangiocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A071.