{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T02:34:39Z","timestamp":1781231679748,"version":"3.54.1"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Biliary tract cancers (BTC) represent a heterogeneous group of malignancies with a poor prognosis and rising incidence. Oncogenic FGFR2 fusions are one of several actionable molecular alterations. In this context, selective FGFR tyrosine kinase inhibitors have demonstrated promising and durable response rates and are now approved and included in clinical guidelines. However, secondary kinase mutations frequently arise over time, leading to resistance against these drugs. We present the case of a 41-year-old male patient with metastatic BTC who underwent molecular analysis after disease progression to various established chemotherapy combinations. Testing identified an oncogenic FGFR2 fusion (FGFR2::BICC1). The patient was treated with pemigatinib for 14\u2009months. Upon disease progression, the resistance-associated FGFR2 p. E565A variant was detected in a follow-up biopsy. Treatment was switched to futibatinib, resulting in rapid disease progression. Lacking other therapeutic options, the patient was treated with lenvatinib, supported by previously published data suggesting a potential benefit in similar settings. The treatment was well tolerated, with only a mild increase in transaminases, and the patient remained on treatment with noteworthy effects for 15\u2009months to date. With a growing incidence of BTC and growing use of targeted therapies for FGFR2 alterations, the emergence of secondary resistance-causing point mutations following treatment with approved inhibitors is becoming increasingly challenging. Beyond selective inhibitors, lenvatinib may represent a viable therapeutic option.<\/jats:p>","DOI":"10.1093\/oncolo\/oyaf322","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T12:14:29Z","timestamp":1759320869000},"source":"Crossref","is-referenced-by-count":1,"title":["Lenvatinib after progression on pemigatinib and futibatinib in FGFR2 fusion-positive biliary tract cancer with an acquired kinase point mutation"],"prefix":"10.1093","volume":"30","author":[{"given":"Fabian","family":"Kleinhenz","sequence":"first","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-5375","authenticated-orcid":false,"given":"Nicole","family":"Pfarr","sequence":"additional","affiliation":[{"name":"Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich , Munich 81675,","place":["Germany"]},{"name":"Center for Personalized Medicine, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Steinhelfer","sequence":"additional","affiliation":[{"name":"Department of Radiology, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa M","family":"L\u00f6rsch","sequence":"additional","affiliation":[{"name":"Center for Personalized Medicine, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Clinical Department of Internal Medicine III, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Bavarian Cancer Research Center (BZKF) , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriette","family":"Bendz","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Liesenfeld","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Barroux","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Maurer","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Kestler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Ulm , Ulm 89081,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai-Lan","family":"Koppermann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Mogler","sequence":"additional","affiliation":[{"name":"Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich , Munich 81675,","place":["Germany"]},{"name":"Center for Personalized Medicine, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Spahn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital, Eberhard-Karls University , 72076 Tuebingen,","place":["Germany"]},{"name":"Center for Personalized Medicine, Eberhard-Karls University , Tuebingen 72076,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L","family":"Illert","sequence":"additional","affiliation":[{"name":"Center for Personalized Medicine, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Clinical Department of Internal Medicine III, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Bavarian Cancer Research Center (BZKF) , Munich 81675,","place":["Germany"]},{"name":"Department of Hematology and Medical Oncology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland M","family":"Schmid","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bitzer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital, Eberhard-Karls University , 72076 Tuebingen,","place":["Germany"]},{"name":"Center for Personalized Medicine, Eberhard-Karls University , Tuebingen 72076,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0406-1401","authenticated-orcid":false,"given":"Sebastian","family":"Lange","sequence":"additional","affiliation":[{"name":"Clinical Department of Internal Medicine II, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Center for Personalized Medicine, TUM School of Medicine and Health, TUM University Hospital , Munich 81675,","place":["Germany"]},{"name":"Bavarian Cancer Research Center (BZKF) , Munich 81675,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"2025102708070530900_oyaf322-B1","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1159\/000453013","article-title":"Epidemiology and risk factors of cholangiocarcinoma","volume":"32","author":"Kirstein","year":"2016","journal-title":"Visc Med."},{"key":"2025102708070530900_oyaf322-B2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/nrclinonc.2017.157","article-title":"Cholangiocarcinoma\u2014evolving concepts and therapeutic strategies","volume":"15","author":"Ilyas","year":"2018","journal-title":"Nat Rev Clin Oncol."},{"key":"2025102708070530900_oyaf322-B3","doi-asserted-by":"publisher","first-page":"e92","DOI":"10.1055\/a-2026-1240","article-title":"S3-Leitlinie diagnostik und therapie bili\u00e4rer karzinome\u2014langversion","volume":"61","author":"Bitzer","year":"2023","journal-title":"Z Gastroenterol."},{"key":"2025102708070530900_oyaf322-B4","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1136\/gutjnl-2011-301748","article-title":"Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update","volume":"61","author":"Khan","year":"2012","journal-title":"Gut."},{"key":"2025102708070530900_oyaf322-B5","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med."},{"key":"2025102708070530900_oyaf322-B6","doi-asserted-by":"publisher","first-page":"EVIDoa2200015","DOI":"10.1056\/EVIDoa2200015","article-title":"Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer","volume":"1","author":"Oh","year":"2022","journal-title":"NEJM Evid."},{"key":"2025102708070530900_oyaf322-B7","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/S0140-6736(21)00153-7","article-title":"Biliary tract cancer","volume":"397","author":"Valle","year":"2021","journal-title":"Lancet."},{"key":"2025102708070530900_oyaf322-B8","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1200\/JCO.21.00679","article-title":"Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): a randomized phase II study","volume":"40","author":"Phelip","year":"2022","journal-title":"J Clin Oncol."},{"key":"2025102708070530900_oyaf322-B9","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1158\/2159-8290.CD-16-1000","article-title":"Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 Fusion-Positive cholangiocarcinoma","volume":"7","author":"Goyal","year":"2017","journal-title":"Cancer Discov."},{"key":"2025102708070530900_oyaf322-B10","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1038\/s41416-022-01908-1","article-title":"Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing","volume":"127","author":"Neumann","year":"2022","journal-title":"Br J Cancer."},{"key":"2025102708070530900_oyaf322-B11","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1146\/annurev-med-042921-024707","article-title":"FGFR2 inhibition in cholangiocarcinoma","volume":"74","author":"Vogel","year":"2023","journal-title":"Annu Rev Med."},{"key":"2025102708070530900_oyaf322-B12","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1158\/1078-0432.CCR-23-1317","article-title":"Landscape of clinical resistance mechanisms to FGFR inhibitors in FGFR2-altered cholangiocarcinoma","volume":"30","author":"Wu","year":"2024","journal-title":"Clin Cancer Res."},{"key":"2025102708070530900_oyaf322-B13","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1158\/2159-8290.CD-19-0182","article-title":"TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma","volume":"9","author":"Goyal","year":"2019","journal-title":"Cancer Discov."},{"key":"2025102708070530900_oyaf322-B14","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.molcel.2007.06.028","article-title":"A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases","volume":"27","author":"Chen","year":"2007","journal-title":"Mol Cell."},{"key":"2025102708070530900_oyaf322-B15","doi-asserted-by":"publisher","first-page":"4943","DOI":"10.1158\/1078-0432.CCR-24-1834","article-title":"Understanding and overcoming resistance to selective FGFR inhibitors across FGFR2-driven malignancies","volume":"30","author":"Facchinetti","year":"2024","journal-title":"Clin Cancer Res."},{"key":"2025102708070530900_oyaf322-B16","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.annonc.2024.12.011","article-title":"A model for decoding resistance in precision oncology: acquired resistance to FGFR inhibitors in cholangiocarcinoma","volume":"36","author":"Goyal","year":"2025","journal-title":"Ann Oncol."},{"key":"2025102708070530900_oyaf322-B17","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1158\/1535-7163.MCT-19-0631","article-title":"Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma","volume":"19","author":"Krook","year":"2020","journal-title":"Mol Cancer Ther."},{"key":"2025102708070530900_oyaf322-B18","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.1158\/2159-8290.CD-23-0475","article-title":"RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations","volume":"13","author":"Subbiah","year":"2023","journal-title":"Cancer Discov."},{"key":"2025102708070530900_oyaf322-B19","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1056\/NEJMoa2206834","article-title":"Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma","volume":"388","author":"Goyal","year":"2023","journal-title":"N Engl J Med."},{"key":"2025102708070530900_oyaf322-B20","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1038\/s41467-024-45247-6","article-title":"The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma","volume":"15","author":"Spahn","year":"2024","journal-title":"Nat Commun."},{"key":"2025102708070530900_oyaf322-B21","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.jhep.2022.11.005","article-title":"Integrating cytotoxic, targeted and immune therapies for cholangiocarcinoma","volume":"78","author":"Merters","year":"2023","journal-title":"J Hepatol."},{"key":"2025102708070530900_oyaf322-B22","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1200\/JCO.2021.39.3_suppl.321","article-title":"Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study","volume":"39","author":"Villanueva","year":"2021","journal-title":"J Clin Oncol."},{"key":"2025102708070530900_oyaf322-B23","doi-asserted-by":"publisher","first-page":"103919","DOI":"10.1016\/j.esmoop.2024.103919","article-title":"Phase I\/II study of nivolumab plus lenvatinib for advanced biliary tract cancer (JCOG1808\/NCCH1817, SNIPE)","volume":"9","author":"Ueno","year":"2024","journal-title":"ESMO Open."}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/advance-article-pdf\/doi\/10.1093\/oncolo\/oyaf322\/64464422\/oyaf322.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/30\/10\/oyaf322\/64464422\/oyaf322.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/30\/10\/oyaf322\/64464422\/oyaf322.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:07:12Z","timestamp":1761566832000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/doi\/10.1093\/oncolo\/oyaf322\/8270667"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,1]]},"references-count":23,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyaf322","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,10,1]]},"article-number":"oyaf322"}}