{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T17:40:12Z","timestamp":1794591612248,"version":"4.9.1"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Egypt Natl Canc Inst"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy often diagnosed at an advanced stage. For over a decade, gemcitabine-cisplatin (GemCis) remained the standard of care with limited survival benefit. The advent of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape, but variability in outcomes and a rapidly expanding evidence base require systematic synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic review was conducted following PRISMA 2020 guidelines. The review was not registered in PROSPERO or another prospective registry. PubMed\/MEDLINE and Embase were searched from inception through 31 December 2024. Studies evaluating PD-1\/PD-L1\/CTLA-4 inhibitors alone or in combination for advanced CCA were included. Risk of bias was assessed using ROBINS-I for non-randomized studies and Cochrane RoB 2 for randomized controlled trials. A narrative synthesis was performed due to clinical and methodological heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifty-one studies (\u2248\u20094,800 patients) met inclusion criteria, including 8 randomized controlled trials and 43 non-randomized studies. First-line chemo-immunotherapy with durvalumab or pembrolizumab plus GemCis established new standards of care in TOPAZ-1 (mOS 12.9 vs. 11.3 months; HR 0.76) and KEYNOTE-966 (mOS 12.7 vs. 10.9 months; HR 0.83). Triplet regimens (chemotherapy\u2009+\u2009ICI\u2009+\u2009tyrosine kinase inhibitor [TKI]) demonstrated high activity (e.g., toripalimab\u2009+\u2009lenvatinib\u2009+\u2009GEMOX: ORR 80%, mOS 22.5 months). Second-line ICI monotherapy yielded modest ORRs (3\u201322%), while ICI\u2009+\u2009TKI combinations showed ORRs of 9\u201328%. Grade\u2009\u2265\u20093 treatment-related adverse events ranged from 10 to 17% (ICI monotherapy) to 70\u201375% (chemo-ICI). PD-L1 expression was not predictive in chemo-ICI; homologous recombination deficiency (HRD)\/DNA damage response (DDR) mutations and circulating tumor DNA (ctDNA) clearance emerged as promising biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ICIs combined with chemotherapy have redefined first-line treatment for advanced CCA. Triplet and locoregional combinations show encouraging efficacy, warranting further validation. Biomarker-driven selection, particularly HRD\/DDR status and ctDNA monitoring, will be critical to optimizing outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s43046-026-00381-8","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T12:14:50Z","timestamp":1783340090000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune checkpoint inhibitors in advanced cholangiocarcinoma: a systematic review of efficacy, safety, and emerging biomarkers"],"prefix":"10.1186","volume":"38","author":[{"given":"Faiz Un","family":"Nisa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moeez","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talha","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muskan","family":"Lohana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniba","family":"Asif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandni","family":"Kumari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaz","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"issue":"8","key":"381_CR1","doi-asserted-by":"publisher","first-page":"EVIDoa2200015","DOI":"10.1056\/EVIDoa2200015","volume":"1","author":"DY Oh","year":"2022","unstructured":"Oh DY, He AR, Qin S, Chen LT, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8):EVIDoa2200015.","journal-title":"NEJM Evid"},{"issue":"1","key":"381_CR2","doi-asserted-by":"publisher","first-page":"e000367","DOI":"10.1136\/jitc-2019-000367","volume":"8","author":"K Feng","year":"2020","unstructured":"Feng K, Liu Y, Zhao Y, Yang Q, Dong L, Liu J, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study. J Immunother Cancer. 2020;8(1):e000367.","journal-title":"J Immunother Cancer"},{"issue":"10","key":"381_CR3","doi-asserted-by":"publisher","first-page":"103919","DOI":"10.1016\/j.esmoop.2024.103919","volume":"9","author":"M Ueno","year":"2024","unstructured":"Ueno M, Morizane C, Ikeda M, Ozaka M, Nagashima F, Kataoka T, et al. Phase I\/II study of nivolumab plus lenvatinib for advanced biliary tract cancer (JCOG1808\/NCCH1817, SNIPE). 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This study is a systematic review of previously published literature and did not involve any direct human or animal participants, patient interventions, or collection of primary data. Therefore, ethical approval and individual informed consent were not required.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. This manuscript does not contain any individual person\u2019s data (e.g., images, videos, clinical details, or patient identifiers) in any form. No consent for publication is required.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"42"}}