Abstract 2275: Detection of IDH1 mutations in plasma cell-free circulating tumor DNA (ctDNA) from patients with cholangiocarcinoma
Authors: Aguado-Fraile Elia , Choe Sung , Gliser Camelia , Steelman Lori , Jiang Liewen , Fan Bin , Le Kha , Lowery Maeve A. , Pandya Susan , Wu Bin 
Published: August 2019

Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene are detected in 13-15% of cholangiocarcinoma (CC) cases overall and up to ~25% of intrahepatic CC cases. Ivosidenib (AG-120) is a first-in-class, oral, potent, reversible, targeted inhibitor of the mutant IDH1 (mIDH1) protein, and AG-881 is an oral, potent inhibitor of both mIDH1 and mIDH2. Phase 1 studies for both molecules in patients with mIDH1/2 solid tumors, including CC, have completed enrollment, and analyses are ongoing (AG120-C-002 [NCT02073994]; AG881-C-002 [NCT02481154). Patients with mIDH1 CC were enrolled into the clinical studies based on local tissue testing for the IDH1 mutation. In this work, we examined the feasibility of mIDH1 detection in ctDNA from patients with mIDH1 CC, and explored the correlation with detection by tissue-based next-generation sequencing (NGS) assays and with plasma levels of the oncometabolite D-2-hydroxyglutarate (2-HG). Baseline plasma samples were collected from a total of 41 patients, including 28 from AG120-C-002 and 13 from AG881-C-002. A BEAMing digital PCR platform (Sysmex) was used for the detection and quantification of five mIDH1 alleles, including R132C, R132H, R132L, R132S, and R132G, with 0.02% analytical sensitivity (0.04% for R132H). Tumor tissues were available from 35 of 41 patients and analyzed using the FoundationOne and/or Personalis ACE cancer research targeted panel. Additionally, baseline plasma levels of 2-HG were measured and correlated with plasma mIDH1 ctDNA. Detection of mIDH1 in plasma ctDNA was concordant with IDH1 mutation status by central testing of tissue in 32 of 35 patients (91.4%), with 31 mIDH1-positive results from both plasma and tissue (88.6%). One patient was mIDH1-negative in both plasma and tumor. In all 31 mIDH1-positive cases, the mIDH1 allele detected was concordant. In general, mIDH1 variant allele frequency (VAF) was lower in plasma than in tumor tissue (mean VAF 2.9% in plasma, 26.2% in tumor). Additionally, the level of plasma ctDNA mIDH1 VAF was significantly correlated with baseline plasma 2-HG concentration (Spearman R=0.535, p=0.0009). Correlation with clinical outcome is currently being explored and will be presented. Taken together, our results demonstrate the feasibility of IDH1-R132 mutation detection in plasma from CC patients, with a 91.4% concordance rate with detection in tumor tissue. These results provide a rationale for exploring liquid biopsy-based testing methods when the feasibility of repeated biopsies or sample exhaustion limits the ability to detect actionable mutations through tissue-based NGS panels, which can be a major challenge for trial participation in this indication. Confirmatory liquid biopsy studies will be conducted with baseline and longitudinal samples collected from the ongoing phase 3 study of ivosidenib in mIDH1 CC (NCT02989857).

Citation Format: Elia Aguado-Fraile, Sung Choe, Camelia Gliser, Lori Steelman, Liewen Jiang, Bin Fan, Kha Le, Maeve A. Lowery, Susan Pandya, Bin Wu. Detection of IDH1 mutations in plasma cell-free circulating tumor DNA (ctDNA) from patients with cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2275.