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Futibatinib is a potent, covalent FGFR1\u20134 inhibitor approved for locally advanced\/metastatic cholangiocarcinoma with\n                      <jats:italic>FGFR2<\/jats:italic>\n                      fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effect of futibatinib\u2009\u00b1\u2009MEKi on cell signaling and proliferation of\n                      <jats:italic>KRAS<\/jats:italic>\n                      mt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a \u201c3\u2009+\u20093\u201d dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in\n                      <jats:italic>KRAS<\/jats:italic>\n                      mt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16\u00a0mg QD plus binimetinib 15\u00a0mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an\n                      <jats:italic>FGFR2<\/jats:italic>\n                      fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib\/binimetinib due to reversible retinopathies.<\/jats:p>\n                    <jats:p>Trial register number.<\/jats:p>\n                    <jats:p>NCT04965818.<\/jats:p>\n                    <jats:p>Trial registration date.<\/jats:p>\n                    <jats:p>20-September-2021.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10637-026-01618-y","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:33:49Z","timestamp":1779096829000},"page":"295-304","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical and clinical evaluation of futibatinib in combination with binimetinib in patients with advanced cancer"],"prefix":"10.1007","volume":"44","author":[{"given":"Jordi","family":"Rodon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"O\u2019Neil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natraj R.","family":"Ammakkanavar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Torrado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Hirai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Miura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanae","family":"Hangai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Wacheck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"1618_CR1","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1158\/2159-8290.Cd-15-1377","volume":"6","author":"H Kitai","year":"2016","unstructured":"Kitai H, Ebi H, Tomida S et al (2016) Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. 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The protocol and all clinical trial\u2013related materials were approved by the institutional review board at each investigational site.","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All patients provided written informed consent.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"J.R., B.O.\u2019N., C.L., N.R.A., and C.T. have no competing interests to declare. K.M., H.H., and A.M. are employees of Taiho Pharmaceutical Co. Ltd. B.A., L.J., N.H., A.L., and V.W. are employees of Taiho Oncology, Inc. L.R. received research funding for UCLA Medical Center from Taiho Oncology, Inc.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}