552 Characteristics of the tumor microenvironment in IDH1-mutated cholangiocarcinoma patients from ClarIDHy trial

BackgroundSomatic isocitrate dehydrogenase 1 mutations (IDH1m) convert α-ketoglutarate to the oncogenic metabolite R-2-hydroxyglutarate (2-HG). IDH1m are detected in approximately 13% of intrahepatic cholangiocarcinomas (CCAs).1 Ivosidenib, an oral inhibitor of the IDH1m protein inhibits 2-HG and restores immune response in CCA.2 We analyzed pre-treatment samples, using machine learning models to quantify histologic features of the CCA tumor microenvironment, enabling identification of correlates of IDH1m status, early disease progression (patients experienced progression or death within 1.54 months), and plasma 2-HG levels (median, 630 ng/ml).MethodsA set of H&E images, including from ClarIDHy3, a phase 3 placebo controlled clinical trial of ivosidenib in IDH1m CCA, were split into training/validation (n=200) and test sets for model development. Whole slide images were annotated by GI pathologists to identify and quantify more than 500 different human interpretable features (HIFs), including cell (cancer cell, lymphocyte, macrophage, plasma cell, fibroblast) and tissue (cancer epithelium, stroma, necrosis) features. Utilizing IDH1m and wild type (WT) screening samples, multivariate logistic regression models were trained to predict IDH1m status. P-values were calculated by univariate logistic regression and corrected for multiple comparisons via adjustment for FDR.ResultsA HIF-based multivariate model discriminated between IDH1m and WT CCA (AUC, 0.83; 95% CI, 0.74-0.92). IDH1m was associated with a lower proportion of lymphocytes throughout the tumor (OR, 0.64; P