{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:28:45Z","timestamp":1793064525185,"version":"4.5.0"},"reference-count":10,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"<jats:sec id=\"ab-zoi230784-4\"><jats:title>Importance<\/jats:title><jats:p>Anti\u2013programmable cell death-1 (anti\u2013PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti\u2013PD-1.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi230784-5\"><jats:title>Objective<\/jats:title><jats:p>To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti\u2013PD-1 therapy.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi230784-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This retrospective multicenter cohort study analyzed patients treated with adjuvant anti\u2013PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months).<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi230784-7\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi230784-8\"><jats:title>Results<\/jats:title><jats:p>Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti\u2013PD-1 start and 11.2 [8.1-20.7] months from anti\u2013PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi230784-9\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this cohort study of 318 patients who received adjuvant anti\u2013PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.27145","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T15:32:55Z","timestamp":1691076775000},"page":"e2327145","source":"Crossref","is-referenced-by-count":79,"title":["Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti\u2013PD-1 Therapy for High-Risk Resected Melanoma"],"prefix":"10.1001","volume":"6","author":[{"given":"Rachel S.","family":"Goodman","sequence":"first","affiliation":[{"name":"Vanderbilt University School of Medicine, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleigha","family":"Lawless","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Woodford","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Melanoma Institute of Australia, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faisal","family":"Fa\u2019ak","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York University School of Medicine, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asha","family":"Tipirneni","sequence":"additional","affiliation":[{"name":"Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Randall","family":"Patrinely","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui Ling","family":"Yeoh","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suthee","family":"Rapisuwon","sequence":"additional","affiliation":[{"name":"Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Haydon","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Osman","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York University School of Medicine, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice M.","family":"Mehnert","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York University School of Medicine, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina V.","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo S.","family":"Carlino","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Blacktown and Westmead Hospitals, Melanoma Institute of Australia"},{"name":"The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Menzies","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia, Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas B.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"issue":"36","key":"zoi230784r1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.36_suppl.356154","article-title":"DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial\u2014ECOG-ACRIN EA6134.","volume":"39","author":"Atkins","year":"2021","journal-title":"J Clin Oncol"},{"issue":"10304","key":"zoi230784r2","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/S0140-6736(21)01206-X","article-title":"Immune checkpoint inhibitors in melanoma.","volume":"398","author":"Carlino","year":"2021","journal-title":"Lancet"},{"issue":"19","key":"zoi230784r3","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1056\/NEJMoa1802357","article-title":"Adjuvant pembrolizumab versus placebo in resected stage iii melanoma.","volume":"378","author":"Eggermont","year":"2018","journal-title":"N Engl J Med"},{"issue":"11","key":"zoi230784r4","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/S1470-2045(20)30494-0","article-title":"Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.","volume":"21","author":"Ascierto","year":"2020","journal-title":"Lancet Oncol"},{"issue":"3","key":"zoi230784r5","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1158\/2159-8290.CD-21-1141","article-title":"Adjuvant pembrolizumab versus IFNa2b or ipilimumab in resected high-risk melanoma.","volume":"12","author":"Grossmann","year":"2022","journal-title":"Cancer Discov"},{"issue":"16","key":"zoi230784r6","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1001\/jama.2018.13995","article-title":"Immune checkpoint inhibitor toxicity in 2018.","volume":"320","author":"Johnson","year":"2018","journal-title":"JAMA"},{"issue":"5","key":"zoi230784r7","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1001\/jamaoncol.2021.0051","article-title":"Chronic immune-related adverse events following adjuvant anti\u2013PD-1 therapy for high-risk resected melanoma.","volume":"7","author":"Patrinely","year":"2021","journal-title":"JAMA Oncol"},{"issue":"4","key":"zoi230784r9","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/s41571-022-00600-w","article-title":"Immune-checkpoint inhibitors: long-term implications of toxicity.","volume":"19","author":"Johnson","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"issue":"12","key":"zoi230784r10","doi-asserted-by":"publisher","first-page":"e967","DOI":"10.1093\/oncolo\/oyac220","article-title":"Recurrence of hypophysitis after immune checkpoint inhibitor rechallenge.","volume":"27","author":"Park","year":"2022","journal-title":"Oncologist"},{"key":"zoi230784r8","unstructured":"Common terminology criteria for adverse events (CTCAE), version 5.0. US Department of Health and Human Serrvices. Accessed June 29, 2023. https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/CTCAE_v5_Quick_Reference_5x7.pdf"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2807931\/goodman_2023_oi_230784_1690380959.6656.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T15:33:12Z","timestamp":1691076792000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2807931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,3]]},"references-count":10,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.27145","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,3]]}}}