Abstract 5346: Prognostic impact and clinical characteristics of <i>KRAS</i> mutations and <i>CDKN2A</i> loss in <i>IDH1</i> -mutant intrahepatic cholangiocarcinoma.

Abstract Background: In the ClarIDHy trial, ivosidenib significantly improved progression-free survival (PFS) compared with placebo in patients with previously treated IDH1-mutant cholangiocarcinoma (CCA) and is currently awaiting insurance approval in Japan. However, approximately 40% of patients in both arms experience disease progression within 2 months, suggesting underlying biological heterogeneity within IDH1-mutant CCA. We hypothesized that genomic co-alterations may serve as potential determinants of this heterogeneity. Methods: We analyzed patients with intrahepatic cholangiocarcinoma (iCCA) in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and June 2025. Point mutations were annotated using OncoKB, and copy number variants and rearrangements were evaluated using C-CAT (approval number CDU2021-001N). Additionally, we reviewed institutional patients with IDH1-mutant iCCA diagnosed between October 2001 and October 2025, with detailed pathological and radiological assessments (approval number 2018-149). Results: Among 2484 patients with iCCA, 353 had IDH1 mutations (14.2%). IDH1-mutant iCCA tended to show longer overall survival (OS) and time to treatment failure (TTF) for first-line therapy than IDH1-wild type (median OS, 22.4 vs. 20.1 months; HR, 0.83; P=0.054; median TTF, 7.8 vs. 6.4 months; HR, 0.87; P=0.068). In IDH1-mutant iCCA, KRAS mutations and CDKN2A loss were less frequent than IDH1-wild type (KRAS mutations, 11.6% vs. 27.6%, P&amp;lt;0.001; CDKN2A loss, 17.8% vs. 27.5%, P&amp;lt;0.001). Among IDH1-mutant iCCA, KRAS mutations showed a trend toward shorter OS (median, 17.0 vs. 23.2; HR, 1.60; P=0.069) and were associated with shorter TTF (median, 5.7 vs. 8.5 months; HR, 1.86; P=0.0039). CDKN2A loss was correlated with shorter OS (median, 17.6 vs. 23.7 months; HR, 1.58; P=0.037). IDH1-mutant iCCA without KRAS mutations or CDKN2A loss demonstrated significantly longer OS (median, 24.9 vs. 17.6 months; HR, 0.61, P=0.010) and TTF (median, 8.4 vs. 6.1 months; HR, 0.70, P=0.020) than the other subsets. In multivariate analysis, KRAS mutations predicted shorter OS (HR, 1.75; P=0.046) and TTF (HR, 1.77; P=0.012). In an institutional cohort of 37 patients, only one case was pathologically classified as large-duct type and harbored KRAS mutation, with all other cases classified as small-duct type. Radiologically, IDH1-mutant iCCA without KRAS mutations and CDKN2A loss tended to present in a peripheral location (60.0% vs. 33.3%) and intratumoral transversing vessels (84.0% vs. 55.6%). Conclusions: IDH1 mutations less frequently co-occur with KRAS mutations and CDKN2A loss. IDH1-mutant iCCA without these co-alterations exhibited favorable clinical outcomes and distinct radiopathological characteristics, highlighting the biological heterogeneity associated with genomic co-alterations in IDH1-mutant iCCA. Citation Format: Eiichiro So, Chigusa Morizane, Kouya Shiraishi, Nobuyoshi Hiraoka, Miyuki Sone, Takafumi Koyama, Rui Kitadai, Yusuke Okuma, Takashi Kohno, Tetsuro Shiraishi, Yuno Goto, Shiho Hakui, Kiyoaki Ochi, Keita Fujisaki, Kazunori Onuma, Yasuhiro Komori, Daiki Yamashige, Mao Okada, Shota Harai, Yuta Maruki, Yasuyuki Kawamoto, Yoshikuni Nagashio, Susumu Hijioka, Hideki Ueno, Kenro Hirata, Takanori Kanai, Takuji Okusaka. Prognostic impact and clinical characteristics of KRAS mutations and CDKN2A loss in IDH1-mutant intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5346.