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• W4308385288 abstract "<h3>Background</h3> Somatic isocitrate dehydrogenase 1 mutations (<i>IDH1</i>m) convert α-ketoglutarate to the oncogenic metabolite R-2-hydroxyglutarate (2-HG). <i>IDH1</i>m 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 <i>IDH1</i>m status, early disease progression (patients experienced progression or death within 1.54 months), and plasma 2-HG levels (median, 630 ng/ml). <h3>Methods</h3> A set of H&E images, including from ClarIDHy³, a phase 3 placebo controlled clinical trial of ivosidenib in <i>IDH1</i>m 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 <i>IDH1</i>m and wild type (WT) screening samples, multivariate logistic regression models were trained to predict <i>IDH1</i>m status. P-values were calculated by univariate logistic regression and corrected for multiple comparisons via adjustment for FDR. <h3>Results</h3> A HIF-based multivariate model discriminated between <i>IDH1m</i> and WT CCA (AUC, 0.83; 95% CI, 0.74-0.92). <i>IDH1</i>m was associated with a lower proportion of lymphocytes throughout the tumor (OR, 0.64; <i>P</i><0.01; FDR <i>P</i>=0.022), and higher proportion of fibroblasts (OR, 1.8; <i>P</i><0.01; FDR <i>P</i>=0.023) and lower proportion of plasma cells in the stroma (OR, 0.68; <i>P</i><0.01; FDR <i>P</i>=0.032 ) (figure 1A). In a subset of samples, CD3 and CD8 staining showed reduced T-lymphocyte infiltration patterns in <i>IDH1</i>m (n=5) samples relative to <i>IDH1</i> WT (n=19) (figure 1B). Early disease progression of enrolled ClarIDHy patients (ivosidenib n=61, placebo n=38) was associated with a higher proportion of macrophages (OR, 1.70; <i>P</i><0.01; FDR <i>P</i>=0.08) and a lower proportion of tumor infiltrating lymphocytes (OR, 0.63; <i>P</i><0.01; FDR <i>P</i>=0.08), (figure 2A). When correcting for treatment effect, the proportion of lymphocytes in the tumor were still associated with improved PFS (<i>P</i>=0.011). Consistent with previously published data², high 2-HG levels were associated with lower numbers of tumor infiltrating lymphocytes (OR, 0.63; <i>P</i>=0.011; FDR <i>P</i>=0.08) (figure 2B). <h3>Conclusions</h3> Quantitative histologic evaluation suggests that pre-treatment <i>IDH1</i>m CCA samples have a colder tumor microenvironment relative to <i>IDH1</i> WT CCA, with an immunosuppressive tumor microenvironment being associated with early progression. Results from this analysis support exploration of combination with immune checkpoint inhibitors. <h3>Trial Registration</h3> NCT02989857 <h3>References</h3> Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. <i>J Gastrointest Oncol</i>. 2019;<b>10</b>(4):751–765. doi: 10.21037/jgo.2019.03.10. Wu MJ, Shi L, Dubrot J, <i>et al</i>. Mutant IDH Inhibits IFN?-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. <i>Cancer Discov</i>. 2022;<b>12</b>(3):812–835. doi: 10.1158/2159-8290.CD-21-1077. Abou-Alfa GK, Macarulla T, Javle MM, <i>et al</i>. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. <i>Lancet Oncol</i>. 2020;<b>21</b>(6):796–807. doi: 10.1016/S1470-2045(20)30157-1. Epub 2020 May 13. Erratum in: Lancet Oncol. 2020 Oct;21(10):e462. <h3>Ethics Approval</h3> This study was done according to the International Conference on Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Approval from the institutional review board and international ethics committee was obtained at each study site. Patients provided written, informed consent before participating in the study." @default.
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• W4308385288 title "552 Characteristics of the tumor microenvironment in IDH1-mutated cholangiocarcinoma patients from ClarIDHy trial" @default.
• W4308385288 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0552" @default.
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