{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T10:45:10Z","timestamp":1792320310104,"version":"4.4.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Durvalumab plus tremelimumab has emerged as a key therapeutic option for unresectable hepatocellular carcinoma (HCC). This study aimed to meticulously monitor and identify its safety profile using real-world data from the Food and Drug Administration Adverse Event Reporting System (FAERS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data were retrieved from the FAERS database for HCC patients who received durvalumab plus tremelimumab between the fourth quarter of 2017 and the fourth quarter of 2024. Significant adverse event (AE) signals were identified using the odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and mu-item gamma Poisson shrinker (MGPS). Time-to-onset (TTO) was analyzed using Kaplan-Meier method and Weibull modeling. Independent risk factors for drug-related mortality were determined via LASSO-Cox regression, and a risk prediction model was developed to assess prognostic value.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Disproportionality signals were identified in 51 preferred terms (PTs) across 16 system organ classes. Notable PTs with strong signals included immune-mediated hepatic disorder, immune-mediated enterocolitis, and cytokine release syndrome. Several unexpected AEs were observed, such as thyrotoxic crisis and ulcerative colitis. Anaphylactic reaction emerged as an unexpected signal and was categorized by the European Medicines Agency as both a designated and important medical event. TTO analysis revealed that most AEs (63.21%) occurred within 30 days of administration, with a median TTO of 25 days. The occurrence of AEs was significantly influenced by age and AE type. Both exploratory LASSO-Cox regression analysis and risk prediction model preliminarily showed that immune thrombocytopenia, immune-mediated dermatitis, immune-mediated enterocolitis, immune-mediated myocarditis, multiple organ dysfunction syndrome, and myocarditis were independent risk factors for drug-related mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This pharmacovigilance study describes the safety profile of durvalumab plus tremelimumab in HCC. The findings may inform clinical monitoring strategies, though prospective studies are warranted for confirmation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1657398","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:58:32Z","timestamp":1761721112000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["A real-world drug safety surveillance study from the FAERS database of hepatocellular carcinoma patients receiving durvalumab in combination with tremelimumab"],"prefix":"10.3389","volume":"16","author":[{"given":"Yang","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingji","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzuo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoshuo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401686","article-title":"Combination therapy with anti\u2013ctla-4 and anti\u2013pd-1 leads to distinct immunologic changes in vivo","volume":"194","author":"Das","year":"2015","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1159\/000503254","article-title":"Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-pd-1\/pd-L1 and anti-ctla-4 antibodies","volume":"8","author":"Kudo","year":"2019","journal-title":"Liver Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2022.2033208","article-title":"Durvalumab: an investigational agent for unresectable hepatocellular carcinoma","volume":"31","author":"Maestri","year":"2022","journal-title":"Expert Opin Investig Drugs"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.1200\/JCO.20.03555","article-title":"Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I\/ii study","volume":"39","author":"Kelley","year":"2021","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.4_suppl.TPS499","article-title":"A phase 1b\/2, open-label study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive)","volume":"40","author":"Dayyani","year":"2022","journal-title":"Am Soc Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-023-01026-9","article-title":"Tremelimumab: A review in advanced or unresectable hepatocellular carcinoma","volume":"19","author":"France","year":"2024","journal-title":"Target Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2025.2550711","article-title":"Tremelimumab for the treatment of hepatocellular carcinoma","volume":"25","author":"Sogbe","year":"2025","journal-title":"Expert Opin Biol Ther"},{"key":"B9","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s13045-019-0779-5","article-title":"Immune checkpoint inhibitors of pd-L1 as cancer therapeutics","volume":"12","author":"Akinleye","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.17.8954","article-title":"Anti\u2013cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment","volume":"26","author":"Fong","year":"2008","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"EVIDoa2100070","DOI":"10.1056\/EVIDoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Abou-Alfa","year":"2022","journal-title":"NEJM evidence"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02745","article-title":"Systemic therapy for advanced hepatocellular carcinoma: asco guideline update","volume":"42","author":"Gordan","year":"2024","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3322\/caac.21596","article-title":"A review of cancer immunotherapy toxicity","volume":"70","author":"Kennedy","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.07.017","article-title":"Outcomes in the asian subgroup of the phase iii randomised himalaya study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"82","author":"Lau","year":"2025","journal-title":"J Hepatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000000374","article-title":"Gastroenterology F-RMCotACo. Reporting adverse drug events","volume":"114","author":"Feagins","year":"2019","journal-title":"Off J Am Coll Gastroenterology| ACG"},{"key":"B16","unstructured":"Fda Adverse Event Reporting System (Faers) Database"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40425-019-0754-2","article-title":"Endocrine toxicity of immune checkpoint inhibitors: A real-world study leveraging us food and drug administration adverse events reporting system","volume":"7","author":"Zhai","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1038\/s41598-025-85831-4","article-title":"A real-world drug safety surveillance study from the faers database of hepatocellular carcinoma patients receiving pembrolizumab alone and plus lenvatinib","volume":"15","author":"Wang","year":"2025","journal-title":"Sci Rep"},{"key":"B19","unstructured":"Introductory Guide Meddra Version 27.1"},{"key":"B20","unstructured":"Designated Medical Events-Signal Management"},{"key":"B21","unstructured":"Eudravigilance System Overview"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2023.07.003","article-title":"Real-world safety of lacosamide: A pharmacovigilance study based on spontaneous reports in the fda adverse event reporting system","volume":"110","author":"Liu","year":"2023","journal-title":"Seizure"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/pds.668","article-title":"A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions","volume":"11","author":"van Puijenbroek","year":"2002","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (Prrs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050466","article-title":"A bayesian neural network method for adverse drug reaction signal generation","volume":"54","author":"Bate","year":"1998","journal-title":"Eur J Clin Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200225060-00001","article-title":"Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the us fda\u2019s spontaneous reports database","volume":"25","author":"Szarfman","year":"2002","journal-title":"Drug Saf"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1320458","article-title":"A real-world pharmacovigilance study of mepolizumab in the fda adverse event reporting system (Faers) database","volume":"14","author":"Zou","year":"2023","journal-title":"Front Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1200254","article-title":"A real-world pharmacovigilance analysis of fda adverse event reporting system database for upadacitinib","volume":"14","author":"Wu","year":"2023","journal-title":"Front Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/pds.964","article-title":"Comparison of data mining methodologies using Japanese spontaneous reports","volume":"13","author":"Kubota","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B30","doi-asserted-by":"publisher","first-page":"g6284","DOI":"10.1136\/bmj.g6284","article-title":"Multiple hypothesis testing and bonferroni\u2019s correction","volume":"349","author":"Sedgwick","year":"2014","journal-title":"Bmj"},{"key":"B31","doi-asserted-by":"publisher","first-page":"21","DOI":"10.2165\/00002018-200831010-00003","article-title":"Methods for causality assessment of adverse drug reactions: A systematic review","volume":"31","author":"Agbabiaka","year":"2008","journal-title":"Drug Saf"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2024.10.013","article-title":"Glucagon-like peptide-1 receptor agonists and impaired gastric emptying: A pharmacovigilance analysis of the us food and drug administration adverse event reporting system","volume":"134","author":"Huang","year":"2025","journal-title":"Br J Anaesth"},{"key":"B33","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s40264-013-0061-7","article-title":"Illustration of the weibull shape parameter signal detection tool using electronic healthcare record data","volume":"36","author":"Sauzet","year":"2013","journal-title":"Drug Saf"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1485190","article-title":"A real-world pharmacovigilance analysis of adverse events associated with irbesartan using the faers and jader databases","volume":"15","author":"Liu","year":"2024","journal-title":"Front Pharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1231320","article-title":"Risk factors for drug-related acute pancreatitis: an analysis of the fda adverse event reporting system (Faers)","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.03.033","article-title":"Five-year overall survival update from the himalaya study of tremelimumab plus durvalumab in unresectable hcc","volume":"83","author":"Rimassa","year":"2025","journal-title":"J Hepatol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"397","DOI":"10.3892\/ol.2024.14530","article-title":"Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real\u2212World practice","volume":"28","author":"Shimose","year":"2024","journal-title":"Oncol Lett"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s11096-023-01678-7","article-title":"Exploring the safety profile of tremelimumab: an analysis of the fda adverse event reporting system","volume":"46","author":"Zhao","year":"2024","journal-title":"Int J Clin Pharm"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-025-01583-1","article-title":"A pharmacovigilance analysis of post-marketing safety of durvalumab","volume":"15","author":"Tan","year":"2025","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2147\/JHC.S420603","article-title":"Updates in characteristics and survival rates of hepatocellular carcinoma in a nationwide cohort of real-world us patients, 2003\u20132021","volume":"10","author":"Tran","year":"2023","journal-title":"J Hepatocell Carcinoma"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1186\/s12885-025-14696-7","article-title":"Adverse drug reaction to tremelimumab and durvalumab in hepatocellular carcinoma patients: an analysis of the food and drug administration adverse event reporting system database","volume":"25","author":"Sui","year":"2025","journal-title":"BMC Cancer"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1631273","article-title":"Evaluating the toxicity profile of combination immune checkpoint inhibitors: A disproportionality analysis of real-world adverse events from the fda adverse event reporting system (Faers) for tremelimumab, durvalumab, ipilimumab, and nivolumab","volume":"16","author":"Li","year":"2025","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"21055","DOI":"10.1038\/s41598-025-07287-w","article-title":"Disproportionality analysis of adverse events associated with ipilimumab and nivolumab combination therapy based on faers database","volume":"15","author":"Dai","year":"2025","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.06.025","article-title":"Interferon-gamma\u2013producing cd8+ Tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor\u2013colitis","volume":"161","author":"Sasson","year":"2021","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e31828f1d51","article-title":"Ipilimumab-induced perforating colitis","volume":"47","author":"Mitchell","year":"2013","journal-title":"J Clin Gastroenterol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00730","article-title":"Immune-related adverse events associated with anti-pd-1\/pd-L1 treatment for Malignancies: A meta-analysis","volume":"8","author":"Wang","year":"2017","journal-title":"Front Pharmacol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01808","article-title":"Incidence of cardiovascular events in patients treated with immune checkpoint inhibitors","volume":"40","author":"Laenens","year":"2022","journal-title":"J Clin Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609214","article-title":"Fulminant myocarditis with combination immune checkpoint blockade","volume":"375","author":"Johnson","year":"2016","journal-title":"N Engl J Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.10.021","article-title":"Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma","volume":"72","author":"Sangro","year":"2020","journal-title":"J Hepatol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-1983","article-title":"Exposure-response analyses of tremelimumab monotherapy or in combination with durvalumab in patients with unresectable hepatocellular carcinoma","volume":"29","author":"Song","year":"2023","journal-title":"Clin Cancer Res"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2021.5476","article-title":"Association of cutaneous immune-related adverse events with increased survival in patients treated with anti\u2013programmed cell death 1 and anti\u2013programmed cell death ligand 1 therapy","volume":"158","author":"Tang","year":"2022","journal-title":"JAMA Dermatol"},{"key":"B53","volume-title":"Astrazeneca Pharmaceuticals Lp","year":"2020"},{"key":"B54","volume-title":"Astrazeneca Pharmaceuticals Lp","year":"2022"},{"key":"B55","doi-asserted-by":"publisher","first-page":"989","DOI":"10.3390\/cancers13050989","article-title":"Immune-related adverse events (Irae) in cancer immune checkpoint inhibitors (Ici) and survival outcomes correlation: to rechallenge or not","volume":"13","author":"Albandar","year":"2021","journal-title":"Cancers"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2960","DOI":"10.3748\/wjg.15.2960","article-title":"Systemic abnormalities in liver disease","volume":"15","author":"Minemura","year":"2009","journal-title":"World J Gastroenterol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/jsxmed\/qdae072","article-title":"What is the validity of the federal adverse event reporting system in contemporary clinical research","author":"Ha","year":"2024","journal-title":"Oxford Univ Press"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1515730","article-title":"The real-world safety of ofatumumab: A pharmacovigilance analysis based on the fda adverse event reporting system","volume":"16","author":"Zhou","year":"2025","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1657398\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:58:35Z","timestamp":1761721115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1657398\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,29]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2025.1657398"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1657398","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,29]]},"article-number":"1657398"}}