{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T08:09:23Z","timestamp":1770451763080,"version":"3.49.0"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,12,9]],"date-time":"2017-12-09T00:00:00Z","timestamp":1512777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Gemcitabine\u2010based therapy remains the mainstay of treatment for patients with biliary tract cancers (<jats:styled-content style=\"fixed-case\">BTC<\/jats:styled-content>s) with no second\u2010line treatment(s) established yet. Aberrant activation of the <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> pathway in patients with <jats:styled-content style=\"fixed-case\">BTC<\/jats:styled-content> indicates its importance in <jats:styled-content style=\"fixed-case\">BTC<\/jats:styled-content>. Trametinib is a potent, highly selective, allosteric non\u2010competitive inhibitor of <jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>1\/<jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>2. In this phase <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>a open\u2010label, single\u2010arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced <jats:styled-content style=\"fixed-case\">BTC<\/jats:styled-content> refractory to gemcitabine\u2010based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>), death, or unacceptable toxicity. The primary objective was to determine the 12\u2010week non\u2010<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> rate. Secondary assessments included safety, progression\u2010free survival (<jats:styled-content style=\"fixed-case\">PFS<\/jats:styled-content>), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non\u2010<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> rate at week 12 was 10% (95% confidence interval, 1.2\u201031.7); it did not reach the threshold rate of 25%. Median <jats:styled-content style=\"fixed-case\">PFS<\/jats:styled-content> was 10.6 weeks (95% confidence interval, 4.6\u201012.1) and 1\u2010year overall survival was 20.0%. Stable disease and <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end\u2010point was not met, prolonged <jats:styled-content style=\"fixed-case\">PFS<\/jats:styled-content> was observed in one patient having six somatic variants including synonymous <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1 exon 12 splice variant and a loss\u2010of\u2010function variant in <jats:styled-content style=\"fixed-case\">ARID<\/jats:styled-content>1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.<\/jats:p>","DOI":"10.1111\/cas.13438","type":"journal-article","created":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T19:06:36Z","timestamp":1510254396000},"page":"215-224","source":"Crossref","is-referenced-by-count":45,"title":["Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-2086","authenticated-orcid":false,"given":"Masafumi","family":"Ikeda","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital East Kashiwa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Ioka","sequence":"additional","affiliation":[{"name":"Osaka International Cancer Institute Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Fukutomi","sequence":"additional","affiliation":[{"name":"Shizuoka Cancer Center Shizuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chigusa","family":"Morizane","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiyoshi","family":"Kasuga","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Kyorin University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital East Kashiwa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Todaka","sequence":"additional","affiliation":[{"name":"Shizuoka Cancer Center Shizuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuji","family":"Okusaka","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caretha L.","family":"Creasy","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelby","family":"Gorman","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Felitsky","sequence":"additional","affiliation":[{"name":"Jounce Therapeutics Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikiro","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Novartis Pharma Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanghong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Novartis Pharma Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0663-6117","authenticated-orcid":false,"given":"Junji","family":"Furuse","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Kyorin University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,12,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2007-0252"},{"key":"e_1_2_8_3_1","unstructured":"National Cancer Center.Cancer statistics in Japan 2009. [Accessed January 2016.] Available from:http:\/\/www.fpcr.or.jp\/publication\/statistics.html."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-015-1436-2"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.21037\/cco.2016.10.09"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908721"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605779"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-007-0673-7"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12218"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-010-9553-9"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-013-2106-0"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers3022243"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2012.08.003"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.5.706"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-2388(200009)19:2<84::AID-SSU2>3.0.CO;2-0"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-004-1046-9"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2010.06.009"},{"issue":"4","key":"e_1_2_8_18_1","article-title":"A Phase 1 study of MEK inhibitor MEK162 (ARRY\u2010438162) in patients with biliary tract cancer","volume":"30","author":"Finn RS","year":"2012","journal-title":"J Clin Oncol"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.33.9473"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2200"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10587"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-010-9417-3"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000205388"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-010-9485-4"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu162"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.29471"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.119"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3375"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.05.009"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6696"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.02.033"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2813"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.024"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0817"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-2625"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2092"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2013.05.010"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcas.13438","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.13438","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T05:40:54Z","timestamp":1693978854000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.13438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,9]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1111\/cas.13438"],"URL":"https:\/\/doi.org\/10.1111\/cas.13438","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,9]]}}}