{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:10:14Z","timestamp":1790763014265,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T00:00:00Z","timestamp":1561680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single\u2010institution clinical\/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pembrolizumab was administered at a dose of 200\u00a0mg intravenously every 3\u00a0weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD\u20101), programmed death\u2013ligand 1 (PD\u2010L1), and PD\u2010L2 were correlated with response, tumor PD\u2010L1 expression, and other clinicopathological features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3\/4 adverse events were increases in aspartate aminotransferase and\/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression\u2010free survival was 4.5\u00a0months and the median overall survival was 13\u00a0months. Response did not correlate with prior sorafenib therapy, PD\u2010L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF\u2010\u03b2 levels (\u2265200\u00a0pg\/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD\u2010L1 and plasma PD\u2010L1\/PD\u20101 levels were associated with plasma IFN\u2010\u03b3 or IL\u201010.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD\u2010L1 staining indicated that baseline TGF\u2010\u03b2 could be a predictive biomarker for response to pembrolizumab.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.32339","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T10:01:25Z","timestamp":1561716085000},"page":"3603-3614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":143,"title":["Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma"],"prefix":"10.1002","volume":"125","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7310-2601","authenticated-orcid":false,"given":"Lynn G.","family":"Feun","sequence":"first","affiliation":[{"name":"Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami Florida"},{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjing","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Miami Veterans Affairs Healthcare System Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhi","family":"Wangpaichitr","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia D.","family":"Jones","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami Florida"},{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Richman","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami Florida"},{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Madrazo","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deukwoo","family":"Kwon","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Shared Resource, Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Garcia\u2010Buitrago","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Hosein","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niramol","family":"Savaraj","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Miami Miller School of Medicine Miami Florida"},{"name":"Division of Hematology and Oncology Miami Veterans Affairs Healthcare System Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(04)00058-3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.7412"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.02.022"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31046-2"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2217\/imt-2016-0025"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2217\/mmt-2017-0018"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.12933"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2010.03255.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.06.043"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4384-8"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2063"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.25752"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30351-6"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2244"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.051"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.3.1914"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-315485"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.61.6870"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25501"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0356-4"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1426519"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00961"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13226"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1319-6"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.32339","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32339","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.32339","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32339","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:12:09Z","timestamp":1760289129000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.32339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,28]]},"references-count":24,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2019,10,15]]}},"alternative-id":["10.1002\/cncr.32339"],"URL":"https:\/\/doi.org\/10.1002\/cncr.32339","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,28]]},"assertion":[{"value":"2019-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}