{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:01:11Z","timestamp":1787508071509,"version":"build-2736575974"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ministry of Health and Welfare and the Center of Excellence for Cancer Research","award":["MOHW110\u2011TDU\u2011B\u2011211\u2011144019"],"award-info":[{"award-number":["MOHW110\u2011TDU\u2011B\u2011211\u2011144019"]}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"crossref","award":["V111C-131"],"award-info":[{"award-number":["V111C-131"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Invest New Drugs"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lenvatinib, a multi-tyrosine kinase inhibitor that inhibits vascular endothelial growth factor and fibroblast growth factor receptors pathway, activated the immune response in tumor microenvironment. However, the combination of lenvatinib and anti-PD-1 has been reported in early phase studies. Hence, this study aims to explore the efficacy and toxicity of lenvatinib combined with nivolumab in the real-world setting. Advanced HCC patients who underwent lenvatinib combined with nivolumab (L\u2009+\u2009N group) treatment at Taipei Veterans General Hospital (Taipei, Taiwan) were reviewed between January 2016 and December 2020. Treatment response and outcomes were collected and analyzed.\u00a0A control group with lenvatinib (L group) was also included for comparison. Forty patients were included in L\u2009+\u2009N group and 47 in L group. The L\u2009+\u2009N group demonstrated a higher objective response rate than L group (45.0% vs. 23.4%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03). The L\u2009+\u2009N group also achieved longer PFS (7.5 vs. 4.8\u00a0months,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.05) and OS (22.9 vs. 10.3\u00a0months,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01) than L group. Patients with HBV infection and REFLECT criteria fit demonstrated a trend of better prognosis. The PFS for those with PR, SD and PD groups were 11.2, 6.4, and 2.2\u00a0months and OS were non-reached, 14.6 and 4.7\u00a0months, respectively. Portal vein thrombosis (HR 4.3, 95% C.I. 1.5\u201312.8) and AFP\u2009&gt;\u2009400\u00a0ng\/mL (HR 3.3, 95% C.I. 1.1\u20139.3) were poor prognostic factors and nivolumab used remained a protective factor (HR 0.2, 95% C.I. 0.1\u20130.7). Dermatitis (35.0%), pruritis (27.5%), and hypothyroidism (27.5%) were the common toxicities. Few patients developed grade 3\/4 toxicities, including dermatitis (15%), gastrointestinal bleeding (7.5%), hypertension (5.0%), pneumonitis (2.5%) and stomatitis (2.5%). This is the first real-world data reporting the promising efficacy and tolerable toxicities of lenvatinib combined with nivolumab in advanced HCC. Further randomized trials are prompted.\n                  <\/jats:p>","DOI":"10.1007\/s10637-022-01248-0","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T22:02:17Z","timestamp":1651096937000},"page":"789-797","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience"],"prefix":"10.1007","volume":"40","author":[{"given":"Wen-Chi","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Yuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2011Huang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2011Ping","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-An","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rheun\u2011Chuan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2011Hsiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"San-Chi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,28]]},"reference":[{"key":"1248_CR1","unstructured":"International Agency for Research on Cancer. World Health Organization. Cancer today. Retrieved May 30, 2021, from https:\/\/gco.iarc.fr\/today\/home"},{"key":"1248_CR2","unstructured":"The leading causes of death in Taiwan (2018). Retrieved May 30, 2021, from https:\/\/www.mohw.gov.tw\/cp-16-48057-1.html"},{"issue":"4","key":"1248_CR3","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378\u2013390","journal-title":"N Engl J Med"},{"issue":"10126","key":"1248_CR4","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","volume":"391","author":"M Kudo","year":"2018","unstructured":"Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet (London, England) 391(10126):1163\u20131173","journal-title":"Lancet (London, England)"},{"issue":"1","key":"1248_CR5","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMoa1717002","volume":"379","author":"GK Abou-Alfa","year":"2018","unstructured":"Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW et al (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. 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Lancet (London, England) 389(10088):2492\u20132502","journal-title":"Lancet (London, England)"},{"key":"1248_CR11","doi-asserted-by":"crossref","unstructured":"Zhu AX, Finn RS, Cattan S, Edeline J, Ogasawara S, Palmer DH, Verslype C, Zagonel V, Rosmorduc O, Vogel A\u00a0et al (2018) KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol\u00a036(suppl 4S):abstr 209","DOI":"10.1200\/JCO.2018.36.4_suppl.209"},{"key":"1248_CR12","doi-asserted-by":"publisher","first-page":"v874","DOI":"10.1093\/annonc\/mdz394.029","volume":"30","author":"T Yau","year":"2019","unstructured":"Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Han KH, Harding JJ, Merle P et al (2019) CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). 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BMC Cancer 12:56","journal-title":"BMC Cancer"},{"issue":"6","key":"1248_CR19","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1002\/cam4.1517","volume":"7","author":"M Matsuki","year":"2018","unstructured":"Matsuki M, Hoshi T, Yamamoto Y, Ikemori-Kawada M, Minoshima Y, Funahashi Y, Matsui J (2018) Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med 7(6):2641\u20132653","journal-title":"Cancer Med"},{"issue":"3","key":"1248_CR20","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1159\/000505695","volume":"9","author":"H Deng","year":"2020","unstructured":"Deng H, Kan A, Lyu N, Mu L, Han Y, Liu L, Zhang Y, Duan Y, Liao S, Li S et al (2020) Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma. 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All methods were carried out in accordance with relevant guidelines and regulations. The subject informed consent form is waived by the institutional review board of Taipei Veterans General Hospital, and study\u2011related information could be not informed the subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"NA.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}