{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:34:27Z","timestamp":1791999267352,"version":"4.4.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"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>Background<\/jats:title>\n                    <jats:p>Nivolumab, a human immunoglobulin IgG4 monoclonal antibody targeting PD-1 receptor, received initial FDA approval in 2014 for treating unresectable or metastatic malignant melanoma (MM), followed by approval for metastatic squamous and non-squamous non-small cell lung cancer (NSCLC) in 2015. With expanding clinical applications of nivolumab, comprehensive evaluation of its safety profile in real-world healthcare settings becomes increasingly crucial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We compiled a real-world safety dataset of nivolumab from the FDA Adverse Event Reporting System (FAERS) database, encompassing reports from Q4\u20132014 through Q2 2024. To evaluate the association between nivolumab and adverse events (AEs), we employed four distinct disproportionality analysis methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS) and Bayesian Confidence Propagation Neural Network (BCPNN). Additionally, we utilized Weibull distribution modeling to characterize the temporal risk patterns of identified adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis identified 64,627 AEs reports associated with nivolumab. The most frequently reported AEs included fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. Notably, we detected several potential safety signals not currently listed in the prescribing information: Malignant neoplasm progression, weight decreased, sepsis myocarditis, encephalitis and hypotension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our large-scale pharmacovigilance study identified significant safety signals associated with nivolumab, including previously unrecognized adverse drug reactions. The identification of these safety signals underscores the importance of ongoing post-marketing surveillance for immune checkpoint inhibitors. Future studies should investigate the mechanisms underlying these associations and develop targeted monitoring protocols.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1605958","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T01:16:59Z","timestamp":1748222219000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The real-world safety of Nivolumab: a pharmacovigilance analysis based on the FDA adverse event reporting system"],"prefix":"10.3389","volume":"16","author":[{"given":"Yutong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyue","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyou","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-022-01723-1","article-title":"Nivolumab plus relatlimab: first approval","volume":"82","author":"Paik","year":"2022","journal-title":"Drugs"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00554-X","article-title":"Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab","volume":"23","author":"Malmberg","year":"2022","journal-title":"Lancet Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2023.06.024","article-title":"Relatlimab-nivolumab: A practical overview for dermatologists","volume":"89","author":"Mullick","year":"2023","journal-title":"J Am Acad Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000005805","article-title":"Primary cerebral Malignant melanoma: A case report with literature review","volume":"96","author":"Tang","year":"2017","journal-title":"Med (Baltimore)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2023-256623","article-title":"Unusual case of intraosseous primary intracranial Malignant melanoma","volume":"17","author":"Guarrera","year":"2024","journal-title":"BMJ Case Rep"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/ane.13690","article-title":"Identification of novel signal of clobazam-associated drug reaction with eosinophilia and systemic symptoms syndrome: A disproportionality analysis","volume":"146","author":"Sharma","year":"2022","journal-title":"Acta Neurol Scand"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2174\/1574886318666230228142856","article-title":"Identification of signal of clindamycin associated renal failure acute: A disproportionality analysis","volume":"19","author":"Javed","year":"2024","journal-title":"Curr Drug Saf"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02229","article-title":"Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma","volume":"40","author":"Wolchok","year":"2022","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-year survival with combined nivolumab and ipilimumab in advanced melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0802714","article-title":"Lung cancer","volume":"359","author":"Herbst","year":"2008","journal-title":"New Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1097\/JTO.0b013e3181c5920c","article-title":"Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey","volume":"5","author":"Morgensztern","year":"2010","journal-title":"J thoracic Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/S0140-6736(16)30958-8","article-title":"Lung cancer: current therapies and new targeted treatments","volume":"389","author":"Hirsch","year":"2017","journal-title":"Lancet (London England)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202170","article-title":"Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer","volume":"386","author":"Forde","year":"2022","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2215530","article-title":"Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer","volume":"389","author":"Provencio","year":"2023","journal-title":"N Engl J Med"},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1201\/9781032629940","volume-title":"Signal Analysis in Pharmacovigilance: Principles and Processes","author":"Kumar","year":"2024"},{"key":"B18","doi-asserted-by":"publisher","first-page":"591","DOI":"10.2165\/00002018-200427080-00010","article-title":"Using MedDRA: implications for risk management","volume":"27","author":"Brown","year":"2004","journal-title":"Drug Saf"},{"key":"B19","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":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2546","article-title":"Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children","volume":"95","author":"Rivkees","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2016.1167184","article-title":"Data mining spontaneous adverse drug event reports for safety signals in Singapore - a comparison of three different disproportionality measures","volume":"15","author":"Ang","year":"2016","journal-title":"Expert Opin Drug Saf"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0393","article-title":"Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: A systematic review and meta-analysis","volume":"5","author":"Wang","year":"2019","journal-title":"JAMA Oncol"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.3923","article-title":"Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis [published correction appears in JAMA Oncol. 2018 Dec 1;4(12):1792. doi: 10.1001\/jamaoncol.2018.5346","volume":"4","author":"Wang","year":"2018","journal-title":"JAMA Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0219206","article-title":"Sex and survival in non-small cell lung cancer: A nationwide cohort study","volume":"14","author":"Radkiewicz","year":"2019","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2023.3256","article-title":"Stage-specific risk of recurrence and death from melanoma in Denmark, 2008-2021: A national observational cohort study of 25 720 patients with stage IA to IV melanoma","volume":"159","author":"Helvind","year":"2023","journal-title":"JAMA Dermatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034442","article-title":"Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma [published correction appears in N Engl J Med. 2021 Aug 26;385(9):864. doi: 10.1056\/NEJMx210012","volume":"384","author":"Bajorin","year":"2021","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02212","article-title":"Nivolumab and ipilimumab as maintenance therapy in extensive-disease small-cell lung cancer: checkMate 451","volume":"39","author":"Owonikoko","year":"2021","journal-title":"J Clin Oncol"},{"key":"B29","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":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200389","article-title":"PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis","volume":"188","author":"Tarrio","year":"2012","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.291.5502.319","article-title":"Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice","volume":"291","author":"Nishimura","year":"2001","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nm955","article-title":"Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice","volume":"9","author":"Okazaki","year":"2003","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.5070\/D328257399","article-title":"Interstitial granulomatous dermatitis and concurrent immunotherapy associated encephalitis with nivolumab and ipilimumab","volume":"28","author":"Starling","year":"2022","journal-title":"Dermatol Online J"},{"key":"B34","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/S1470-2045(20)30641-0","article-title":"First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2021 Mar;22(3):e92. doi: 10.1016\/S1470-2045(21)00082-6","volume":"22","author":"Paz-Ares","year":"2021","journal-title":"Lancet Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.41781","article-title":"Multiorgan failure from nivolumab and ipilimumab: A case report and literature review","volume":"15","author":"Brazel","year":"2023","journal-title":"Cureus"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30006-8","article-title":"Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials","volume":"19","author":"D'Angelo","year":"2018","journal-title":"Lancet Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18999\/nagjms.80.2.285","article-title":"Refractory hypotension due to Nivolumab-induced adrenal insufficiency","volume":"80","author":"Tsukizawa","year":"2018","journal-title":"Nagoya J Med Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1186\/s40425-019-0748-0","article-title":"Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma","volume":"7","author":"Gao","year":"2019","journal-title":"J Immunother Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1605958\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T01:17:00Z","timestamp":1748222220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1605958\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2025.1605958"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1605958","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,26]]},"article-number":"1605958"}}