{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T14:38:04Z","timestamp":1782139084135,"version":"3.54.5"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Pembrolizumab is a key drug in the immunotherapy of endometrial cancer (EC) and has improved the prognosis to some extent. However, adverse drug events (ADEs) have hindered the achievement of expected therapeutic outcomes in EC. This study, therefore, aims to investigate the ADEs of pembrolizumab using the FAERS database, offering new insights for clinical practice in EC treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>From the first quarter of 2016 to the first quarter of 2025, ADEs associated with pembrolizumab in EC were collected from the FAERS database. The Reporting Odds Ratio (ROR) was used as the primary analytical method for signal detection. To validate the robustness of the results, three additional algorithms\u2014Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS)\u2014were also applied. ADEs were systematically classified using the Medical Dictionary for Regulatory Activities (MedDRA) into System Organ Classes (SOC) and Preferred Terms (PT), and ranked by both frequency and signal strength.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 2,154 ADEs associated with pembrolizumab in the treatment of EC were retrieved from the FAERS database. The age distribution of ADEs was primarily concentrated in the 65\u201385\u00a0years age group. The reported body weights were mainly in the 50\u2013100\u00a0kg range. The most frequent ADE outcome was hospitalization. The majority of ADEs occurred within 0\u201330\u00a0days after pembrolizumab administration. Identified ADEs involved endocrine system disorders, including Increased Thyroid Hormones (ROR = 9.22), Decreased Thyroid Hormones (ROR = 5.31), and Immune-Mediated Hypothyroidism (ROR = 6.16). Skin and subcutaneous tissue disorders included Pruritic Rash (ROR = 3.16) and Blisters (ROR = 3.06). Liver-related issues included Increased Hepatic Enzymes (ROR = 2.25). These key signals were consistently confirmed by additional disproportionality algorithms, including PRR, BCPNN, and MGPS, reinforcing the robustness of the findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study used the FAERS database to identify frequently reported ADEs associated with pembrolizumab in the treatment of EC, including endocrine system diseases, musculoskeletal system disorders, skin and subcutaneous tissue reactions, and hepatotoxicity. These findings provide crucial evidence for risk stratification and safety monitoring in clinical practice, emphasizing the need for vigilance toward specific organ systems during the 0\u201330-day treatment window.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1622339","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:44Z","timestamp":1755235784000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Real-world study on adverse drug reactions of pembrolizumab in endometrial cancer treatment: insights from the FAERS database"],"prefix":"10.3389","volume":"16","author":[{"given":"Huiping","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yini","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5701","DOI":"10.1093\/bioinformatics\/btaa1009","article-title":"glmGamPoi: fitting Gamma-Poisson generalized linear models on single cell count data","volume":"36","author":"Ahlmann-Eltze","year":"2021","journal-title":"Bioinformatics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"623","DOI":"10.2165\/00002018-200730070-00011","article-title":"Bayesian confidence propagation neural network","volume":"30","author":"Bate","year":"2007","journal-title":"Drug Saf."},{"key":"B3","doi-asserted-by":"publisher","first-page":"k793","DOI":"10.1136\/bmj.K793","article-title":"Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis","volume":"360","author":"Baxi","year":"2018","journal-title":"BMJ"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1001\/jamaoncol.2019.0402","article-title":"Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer","volume":"5","author":"Berner","year":"2019","journal-title":"JAMA Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/imr.13262","article-title":"Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses","volume":"318","author":"Blum","year":"2023","journal-title":"Immunol. Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"102614","DOI":"10.1016\/j.ctrv.2023.102614","article-title":"Novel targets for immune-checkpoint inhibition in cancer","volume":"120","author":"Borgeaud","year":"2023","journal-title":"Cancer Treat. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"a036863","DOI":"10.1101\/cshperspect.A036863","article-title":"New approaches on cancer immunotherapy","volume":"10","author":"Cha","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1016\/S0140-6736(22)00323-3","article-title":"Endometrial cancer","volume":"399","author":"Crosbie","year":"2022","journal-title":"Lancet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e16198","DOI":"10.1111\/liv.16198","article-title":"Immune-mediated liver injury from checkpoint inhibitor: an evolving frontier with emerging challenges","volume":"45","author":"Dara","year":"2025","journal-title":"Liver Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e252668","DOI":"10.1001\/jamanetworkopen.2025.2668","article-title":"Late-onset immune-related adverse events after immune checkpoint inhibitor therapy","volume":"8","author":"Durbin","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1038\/s41591-025-03566-1","article-title":"Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial","volume":"31","author":"Eskander","year":"2025","journal-title":"Nat. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e008591","DOI":"10.1136\/jitc-2023-008591","article-title":"Chronic immune-related adverse events arising from immune checkpoint inhibitors: an update","volume":"12","author":"Fletcher","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"650292","DOI":"10.3389\/fonc.2021.650292","article-title":"Immune checkpoint inhibitor associated hepatotoxicity in primary liver cancer versus other cancers: a systematic review and meta-analysis","volume":"11","author":"Fu","year":"2021","journal-title":"Front. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s40264-024-01423-7","article-title":"The REporting of A disproportionality analysis for DrUg safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV): explanation and elaboration","volume":"47","author":"Fusaroli","year":"2024","journal-title":"Drug Saf."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4023","DOI":"10.1158\/1078-0432.CCR-15-2872","article-title":"Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy","volume":"22","author":"Goldinger","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/EDBK_280503","article-title":"A review of immune checkpoint blockade therapy in endometrial cancer","volume":"40","author":"Green","year":"2020","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"B17","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1111\/cea.14134","article-title":"Does immune checkpoint inhibitor therapy increase the frequency of adverse reactions to concomitant medications?","volume":"52","author":"Hammond","year":"2022","journal-title":"Clin. Exp. Allergy"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1001\/jama.2023.5623","article-title":"Pembrolizumab immunotherapy improved endometrial cancer survival","volume":"329","author":"Harris","year":"2023","journal-title":"JAMA"},{"key":"B19","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.jaad.2015.10.029","article-title":"Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort","volume":"74","author":"Hwang","year":"2016","journal-title":"J. Am. Acad. Dermatol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1620","DOI":"10.1210\/clinem\/dgab829","article-title":"Increased risk of thyroid dysfunction by PD-1 and CTLA-4 blockade in patients without thyroid autoantibodies at baseline","volume":"107","author":"Iwama","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1080\/17425255.2019.1574744","article-title":"Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies","volume":"15","author":"Jennings","year":"2019","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1447021","DOI":"10.3389\/fimmu.2024.1447021","article-title":"Toxicity in the era of immune checkpoint inhibitor therapy","volume":"15","author":"Keam","year":"2024","journal-title":"Front. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"04101","DOI":"10.7189\/jogh.13.04101","article-title":"Understanding and reporting odds ratios as rate-ratio estimates in case-control studies","volume":"13","author":"Kerr","year":"2023","journal-title":"J. Glob. Health"},{"key":"B24","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1158\/1535-7163.MCT-21-0041","article-title":"Innate immune checkpoint inhibitors: the next breakthrough in medical oncology?","volume":"20","author":"Lentz","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"108803","DOI":"10.1016\/j.intimp.2022.108803","article-title":"Adverse and unconventional reactions related to immune checkpoint inhibitor therapy for cancer","volume":"108","author":"Li","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.annonc.2022.05.519","article-title":"Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study","volume":"33","author":"Maio","year":"2022","journal-title":"Ann. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2904","DOI":"10.1200\/JCO.22.02152","article-title":"Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III study 309\/KEYNOTE-775","volume":"41","author":"Makker","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1212\/WNL.0000000000011795","article-title":"Neurologic adverse events of immune checkpoint inhibitors: a systematic review","volume":"96","author":"Marini","year":"2021","journal-title":"Neurology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"105457","DOI":"10.1016\/j.jbspin.2022.105457","article-title":"Musculoskeletal immune-related adverse events in 927 patients treated with immune checkpoint inhibitors for solid cancer","volume":"90","author":"Melia","year":"2023","journal-title":"Jt. Bone Spine"},{"key":"B30","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/ph14010004","article-title":"Improved detection criteria for detecting drug-drug interaction signals using the proportional reporting ratio","volume":"14","author":"Noguchi","year":"2020","journal-title":"Pharm. (Basel)."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.1002\/cncr.34226","article-title":"Pembrolizumab is effective for endometrial cancer","volume":"128","author":"O'Rourke","year":"2022","journal-title":"Cancer."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1111\/bph.16337","article-title":"Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: a year in review","volume":"181","author":"Papapetropoulos","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1200\/JCO.18.02141","article-title":"Treatment outcomes of immune-related cutaneous adverse events","volume":"37","author":"Phillips","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1136\/ard-2022-223792","article-title":"Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis","volume":"82","author":"Pinal-Fernandez","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-related adverse events associated with immune checkpoint blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"804597","DOI":"10.3389\/fimmu.2022.804597","article-title":"Holistic approach to immune checkpoint inhibitor-related adverse events","volume":"13","author":"Poto","year":"2022","journal-title":"Front. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.jaad.2020.09.054","article-title":"Cutaneous adverse events caused by immune checkpoint inhibitors","volume":"85","author":"Quach","year":"2021","journal-title":"J. Am. Acad. Dermatol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41572-020-0160-6","article-title":"Immune-related adverse events of checkpoint inhibitors","volume":"6","author":"Ramos-Casals","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5376","DOI":"10.3748\/wjg.v27.I32.5376","article-title":"Immune checkpoint inhibitor-related hepatotoxicity: a review","volume":"27","author":"Remash","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"102790","DOI":"10.1016\/j.ctrv.2024.102790","article-title":"Locally advanced and metastatic endometrial cancer: current and emerging therapies","volume":"129","author":"Salmon","year":"2024","journal-title":"Cancer Treat. Rev."},{"key":"B41","doi-asserted-by":"publisher","first-page":"40","DOI":"10.7556\/jaoa.2018.007","article-title":"Toxic injury to the gastrointestinal tract after Ipilimumab therapy for advanced melanoma","volume":"118","author":"Shepard","year":"2018","journal-title":"J. Am. Osteopath Assoc."},{"key":"B42","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s43018-024-00730-3","article-title":"Clinical and translational attributes of immune-related adverse events","volume":"5","author":"Suijkerbuijk","year":"2024","journal-title":"Nat. Cancer"},{"key":"B43","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.trecan.2019.05.010","article-title":"Integrative approaches to cancer immunotherapy","volume":"5","author":"Szeto","year":"2019","journal-title":"Trends Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1001\/jamadermatol.2021.0727","article-title":"Association between systemic corticosteroid treatment for cutaneous immune-related adverse events and survival outcomes in patients with advanced cancer","volume":"157","author":"Thompson","year":"2021","journal-title":"JAMA Dermatol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"103851","DOI":"10.1016\/j.critrevonc.2022.103851","article-title":"Advanced and recurrent endometrial cancer: state of the art and future perspectives","volume":"180","author":"Tronconi","year":"2022","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1007\/s00262-021-02855-1","article-title":"Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors","volume":"70","author":"Tyan","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"B47","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1136\/ijgc-2020-001822","article-title":"Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy","volume":"31","author":"van den Heerik","year":"2021","journal-title":"Int. J. Gynecol. Cancer"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1007\/s00262-020-02813-3","article-title":"The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations","volume":"70","author":"Willvonseder","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"B49","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/s41574-021-00484-3","article-title":"Endocrine toxicities of immune checkpoint inhibitors","volume":"17","author":"Wright","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1159238","DOI":"10.3389\/fcimb.2023.1159238","article-title":"Correlation between the intestinal microflora and peripheral blood Th1\/Th2 balance in hypothyroidism during the first half of pregnancy","volume":"13","author":"Wu","year":"2023","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"101619","DOI":"10.1016\/j.tranon.2023.101619","article-title":"The Current status of steroid-refractory immune-checkpoint-inhibitor-related hepatotoxicity","volume":"28","author":"Xing","year":"2023","journal-title":"Transl. Oncol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"eabb7495","DOI":"10.1126\/scitranslmed.abb7495","article-title":"CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice","volume":"13","author":"Yasuda","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.pathol.2019.10.010","article-title":"Unique and distinctive histological features of immunotherapy-related thyroiditis","volume":"52","author":"Zaborowski","year":"2020","journal-title":"Pathology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1622339\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:45Z","timestamp":1755235785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1622339\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":53,"alternative-id":["10.3389\/fphar.2025.1622339"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1622339","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"article-number":"1622339"}}