{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:24:26Z","timestamp":1790076266259,"version":"4.0.1"},"reference-count":29,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,10,26]],"date-time":"2017-10-26T00:00:00Z","timestamp":1508976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2017,11]]},"abstract":"\n Study Objective<\/jats:title>\n \n Ipilimumab, pembrolizumab, and nivolumab are checkpoint inhibitors (\n CPIs<\/jats:styled-content>\n ) that activate T\u2010cell\u2013mediated immune response.\n CPI<\/jats:styled-content>\n can provide durable benefits to some cancer patients with melanoma, renal cell cancer, non\u2013small cell lung cancer, or a growing list of other cancers. However,\n CPI<\/jats:styled-content>\n treatment is also associated with adverse immune\u2010mediated reactions (\n IMRs<\/jats:styled-content>\n ) that can be life\u2010threatening. This pharmacovigilance analysis aims to characterize\n IMR<\/jats:styled-content>\n signals in relation to\n CPI<\/jats:styled-content>\n treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n Retrospective pharmacovigilance disproportionality analysis.<\/jats:p>\n <\/jats:sec>\n \n Data Source<\/jats:title>\n \n U.S. Food and Drug Administration<\/jats:styled-content>\n Adverse Event Reporting System (\n FAERS<\/jats:styled-content>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Measurements and Main Results<\/jats:title>\n \n Adverse event reports submitted to\n FAERS<\/jats:styled-content>\n between 2011 and 2015 were analyzed.\n CPIs<\/jats:styled-content>\n were identified by generic names, and\n IMRs<\/jats:styled-content>\n were identified by Med\n DRA<\/jats:styled-content>\n Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (\n EB<\/jats:styled-content>\n 05\u2010\n EB<\/jats:styled-content>\n 95) were calculated as\n CPI<\/jats:styled-content>\n \u2010\n IMR<\/jats:styled-content>\n association metrics. Signals were defined as metrics with\n EB<\/jats:styled-content>\n 05\u00a0\u2265\u00a02.0. Overall, 1,018\n IMR<\/jats:styled-content>\n events were submitted for\n CPIs<\/jats:styled-content>\n , corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved\n CPI<\/jats:styled-content>\n agents.\n IMRs<\/jats:styled-content>\n consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion\u2010related reactions, 3% nephritis, and 3% other\n IMRs<\/jats:styled-content>\n . Colitis contributed to 63% and 41% of\n IMRs<\/jats:styled-content>\n for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of\n IMRs<\/jats:styled-content>\n for pembrolizumab, for which nephritis and infusion\u2010related reactions were not reported. Signals of\n IMRs<\/jats:styled-content>\n were detected for\n CPIs<\/jats:styled-content>\n as a class (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a012.4) and individual agents: ipilimumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a013.2), nivolumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a015.0), and pembrolizumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a07.3). Colitis and pneumonitis had the strongest signals for\n CPIs<\/jats:styled-content>\n (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a045.6 and\n EB<\/jats:styled-content>\n 05\u00a0=\u00a017.6, respectively). Colitis was the strongest signal for ipilimumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a054.2), and pneumonitis was the strongest signal for nivolumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a048.0) and pembrolizumab (\n EB<\/jats:styled-content>\n 05\u00a0=\u00a021.8).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Cancer immunotherapy with\n CPIs<\/jats:styled-content>\n is associated with a multitude of\n IMRs<\/jats:styled-content>\n , especially colitis and pneumonitis. Individual\n CPIs<\/jats:styled-content>\n had variable\n IMR<\/jats:styled-content>\n signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/phar.2035","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T10:40:24Z","timestamp":1506422424000},"page":"1383-1390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Pharmacovigilance Assessment of Immune\u2010Mediated Reactions Reported for Checkpoint Inhibitor Cancer Immunotherapies"],"prefix":"10.1002","volume":"37","author":[{"given":"Ayad K.","family":"Ali","sequence":"first","affiliation":[{"name":"Global Patient Safety Eli Lilly and Company Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Watson","sequence":"additional","affiliation":[{"name":"Toxicology Eli Lilly and Company Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,26]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.07.005"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2017.08.005"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-53156-4_8"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2016.04.002"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/EdBook_AM.2013.33.e280"},{"key":"e_1_2_5_7_1","volume-title":"Keytruda [package insert]","author":"Merck Sharp & Dohme Corp","year":"2017"},{"key":"e_1_2_5_8_1","volume-title":"Opdivo [package insert]","author":"Bristol\u2010Myers Squibb Company","year":"2017"},{"key":"e_1_2_5_9_1","volume-title":"Yervoy [package insert]","author":"Bristol\u2010Myers Squibb Company","year":"2015"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609214"},{"key":"e_1_2_5_11_1","volume-title":"FDA Adverse Event Reporting System (FAERS): latest quarterly data files","author":"Food and Drug Administration (FDA)"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1612"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S23889"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2016-216228"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2569"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1104621"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv383"},{"key":"e_1_2_5_19_1","first-page":"1","article-title":"Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma","volume":"14","author":"Weber JS","year":"2016","journal-title":"J Clin Oncol"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"issue":"10","key":"e_1_2_5_21_1","first-page":"674","article-title":"PD\u20101\u2010targeted immunotherapy: recent clinical findings","volume":"10","author":"Brahmer JR","year":"2012","journal-title":"Clin Adv Hematol Oncol"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv182"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.31.9624"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.52.2219"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0455-8"},{"key":"e_1_2_5_26_1","unstructured":"World Health Organization (WHO).Nivolumab: reports of type\u20101 diabetes mellitus.WHO Pharmaceutical Newsletter2016;1:10. 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