{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:50:42Z","timestamp":1781311842868,"version":"3.54.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The use of immune checkpoint inhibitors (ICI) has transformed cancer treatment. Subsequent ICI use has become increasingly common following disease progression. We aim to evaluate the safety and tolerability of the sequential ICI treatment modality.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Retrospective review of confirmed carcinoma from January 2014 to December 2018. Patients were categorized into \u201cinitial ICI arm\u201d and \u201csequential ICI arm\u201d defined as patients receiving single, dual or chemo-immunotherapy ICI following an initial ICI regimen. Primary outcome was the development of a new or recurrent immune related adverse event (irAE) during sequential therapy. Secondary outcomes were the number of cycles prior to the development of irAE and grade of irAE.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 483 patients received ICI during the timeframe. Of those, 22 patients received sequential ICI. The diagnoses included ten lung cancer, seven melanoma, four renal cell carcinoma and one bladder cancer. 16 patients received single agent ICI following the initial ICI, three patients received dual ICI following the initial ICI, one patient received chemotherapy-immunotherapy following initial ICI, and two patients received chemo-immunotherapy after dual ICI. Four patients developed new irAE and one patient developed the same irAE on sequential treatment. A higher proportion of patients experienced grade 3 irAE in the sequential arm compared to the initial ICI arm (<jats:italic>p<\/jats:italic>\u2009=\u20090.03). No statistical difference was found between the development of irAE and the number of cycles prior to development of irAE in either treatment groups (<jats:italic>p<\/jats:italic>\u2009=\u20090.5).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our data shows overall safety of sequencing ICI when close monitoring was employed.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-022-04137-4","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T14:09:42Z","timestamp":1655820582000},"page":"2375-2382","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Safety of sequential immune checkpoint inhibitors after prior immune therapy"],"prefix":"10.1007","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4205-8417","authenticated-orcid":false,"given":"Muhammad","family":"Awidi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-5903","authenticated-orcid":false,"given":"Brendan","family":"Connell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-6655","authenticated-orcid":false,"given":"Delaney","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Craven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rojer","family":"Ranjit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Dal\u2019Bo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewena","family":"Maher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seanna Reilly","family":"Daves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna S.","family":"Gunturu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"issue":"30","key":"4137_CR1","doi-asserted-by":"publisher","first-page":"2738","DOI":"10.1200\/JCO.19.00320","volume":"37","author":"H Abu-Sbeih","year":"2019","unstructured":"Abu-Sbeih H, Ali FS, Naqash AR, Owen DH, Patel S, Otterson GA et al (2019) Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis. J Clin Oncol 37(30):2738\u20132745","journal-title":"J Clin Oncol"},{"issue":"2","key":"4137_CR2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001622","volume":"8","author":"M Allouchery","year":"2020","unstructured":"Allouchery M, Lombard T, Martin M, Rouby F, Sassier M, Bertin C et al (2020) Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade \u22652 immune-related adverse events in patients with cancer. J Immunother Cancer 8(2):e001622","journal-title":"J Immunother Cancer"},{"issue":"4","key":"4137_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s11912-020-0894-z","volume":"22","author":"NA Babacan","year":"2020","unstructured":"Babacan NA, Eroglu Z (2020) Treatment options for advanced melanoma after anti-PD-1 therapy. Curr Oncol Rep 22(4):38","journal-title":"Curr Oncol Rep"},{"issue":"8","key":"4137_CR4","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/nrclinonc.2016.58","volume":"13","author":"C Boutros","year":"2016","unstructured":"Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F et al (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13(8):473\u2013486","journal-title":"Nat Rev Clin Oncol"},{"issue":"17","key":"4137_CR5","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","volume":"36","author":"JR Brahmer","year":"2018","unstructured":"Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36(17):1714\u20131768","journal-title":"J Clin Oncol"},{"issue":"9","key":"4137_CR6","doi-asserted-by":"publisher","first-page":"4275","DOI":"10.1073\/pnas.0915174107","volume":"107","author":"MA Curran","year":"2010","unstructured":"Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci 107(9):4275\u20134280","journal-title":"Proc Natl Acad Sci"},{"issue":"36","key":"4137_CR7","doi-asserted-by":"publisher","first-page":"3563","DOI":"10.1200\/JCO.19.01891","volume":"37","author":"J Delyon","year":"2019","unstructured":"Delyon J, Louren\u00e7o N, Vu LT, Allayous C, Baroudjian B, Lebbe C (2019) Recurrence of immune-mediated colitis upon immune checkpoint inhibitor resumption: does time matter? J Clin Oncol 37(36):3563\u20133564","journal-title":"J Clin Oncol"},{"issue":"6","key":"4137_CR8","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1007\/s00280-018-3585-9","volume":"81","author":"K Fujita","year":"2018","unstructured":"Fujita K, Uchida N, Kanai O, Okamura M, Nakatani K, Mio T (2018) Retreatment with pembrolizumab in advanced non-small cell lung cancer patients previously treated with nivolumab: emerging reports of 12 cases. Cancer Chemother Pharmacol 81(6):1105\u20131109","journal-title":"Cancer Chemother Pharmacol"},{"issue":"6","key":"4137_CR9","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1158\/1078-0432.CCR-17-2267","volume":"24","author":"TN Gide","year":"2018","unstructured":"Gide TN, Wilmott JS, Scolyer RA, Long GV (2018) Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clin Cancer Res 24(6):1260\u20131270","journal-title":"Clin Cancer Res"},{"issue":"27","key":"4137_CR10","doi-asserted-by":"publisher","first-page":"3088","DOI":"10.1200\/JCO.19.03315","volume":"38","author":"A Gul","year":"2020","unstructured":"Gul A, Stewart TF, Mantia CM, Shah NJ, Gatof ES, Long Y et al (2020) Salvage ipilimumab and nivolumab in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitors. J Clin Oncol 38(27):3088\u20133094","journal-title":"J Clin Oncol"},{"key":"4137_CR11","doi-asserted-by":"publisher","first-page":"4019","DOI":"10.1007\/s00520-022-06826-9","volume":"30","author":"KS Gunturu","year":"2022","unstructured":"Gunturu KS, Pham TT, Shambhu S, Fisch MJ, Barron JJ, Debono D (2022) Immune checkpoint inhibitors: immune-related adverse events, healthcare utilization, and costs among commercial and Medicare Advantage patients. Support Care Cancer 30:4019\u20134026","journal-title":"Support Care Cancer"},{"issue":"7","key":"4137_CR12","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1200\/JCO.2017.76.0983","volume":"36","author":"M Horiguchi","year":"2018","unstructured":"Horiguchi M, Uno H, Wei L-J (2018) Patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab as a result of adverse events lived significantly longer than patients who continued treatment. J Clin Oncol 36(7):720\u2013721","journal-title":"J Clin Oncol"},{"issue":"2","key":"4137_CR13","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s00432-018-2819-x","volume":"145","author":"A Indini","year":"2019","unstructured":"Indini A, Di Guardo L, Cimminiello C, Prisciandaro M, Randon G, De Braud F et al (2019) Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J Cancer Res Clin Oncol 145(2):511\u2013521","journal-title":"J Cancer Res Clin Oncol"},{"issue":"7_suppl","key":"4137_CR14","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1200\/JCO.2019.37.7_suppl.481","volume":"37","author":"NM Keegan","year":"2019","unstructured":"Keegan NM, Funt SA, Kania BE, Iyer G, Clement JM, McCoy AS et al (2019) Durable clinical benefit from combination ipilimumab (IPI) and nivolumab (NIVO) in anti-PD-1 therapy resistant, platinum resistant metastatic urothelial carcinoma (mUC). J Clin Oncol 37(7_suppl):481","journal-title":"J Clin Oncol"},{"issue":"16","key":"4137_CR15","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","volume":"381","author":"J Larkin","year":"2019","unstructured":"Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD et al (2019) Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381(16):1535\u20131546","journal-title":"N Engl J Med"},{"issue":"1","key":"4137_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40425-017-0273-y","volume":"5","author":"DJ Martini","year":"2017","unstructured":"Martini DJ, Lalani A-KA, Boss\u00e9 D, Steinharter JA, Harshman LC, Hodi FS et al (2017) Response to single agent PD-1 inhibitor after progression on previous PD-1\/PD-L1 inhibitors: a case series. J Immunother Cancer 5(1):1\u20135","journal-title":"J Immunother Cancer"},{"issue":"36","key":"4137_CR17","doi-asserted-by":"publisher","first-page":"4240","DOI":"10.1200\/JCO.20.02295","volume":"38","author":"RR McKay","year":"2020","unstructured":"McKay RR, McGregor BA, Xie W, Braun DA, Wei X, Kyriakopoulos CE et al (2020) Optimized management of nivolumab and ipilimumab in advanced renal cell carcinoma: a response-based phase II study (OMNIVORE). J Clin Oncol 38(36):4240\u20134248","journal-title":"J Clin Oncol"},{"issue":"15_suppl","key":"4137_CR18","doi-asserted-by":"publisher","first-page":"e21552-e","DOI":"10.1200\/JCO.2018.36.15_suppl.e21552","volume":"36","author":"I Mehmi","year":"2018","unstructured":"Mehmi I, Hill J (2018) Ipilimumab with anti PD-1 (nivolumab or pembrolizumab) after progression on first line anti-PD-1 therapy for advanced melanoma. J Clin Oncol 36(15_suppl):e21552-e","journal-title":"J Clin Oncol"},{"issue":"24","key":"4137_CR19","doi-asserted-by":"publisher","first-page":"2647","DOI":"10.1200\/JCO.21.00079","volume":"39","author":"DJ Olson","year":"2021","unstructured":"Olson DJ, Eroglu Z, Brockstein B, Poklepovic AS, Bajaj M, Babu S et al (2021) Pembrolizumab plus ipilimumab following anti-PD-1\/L1 failure in melanoma. J Clin Oncol 39(24):2647\u20132655","journal-title":"J Clin Oncol"},{"issue":"17","key":"4137_CR20","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1200\/JCO.2014.59.4358","volume":"33","author":"MA Postow","year":"2015","unstructured":"Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33(17):1974\u20131982","journal-title":"J Clin Oncol"},{"issue":"10","key":"4137_CR21","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1001\/jamaoncol.2020.2169","volume":"6","author":"P Ravi","year":"2020","unstructured":"Ravi P, Mantia C, Su C, Sorenson K, Elhag D, Rathi N et al (2020) Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma. JAMA Oncol 6(10):1606\u20131610","journal-title":"JAMA Oncol"},{"issue":"9948","key":"4137_CR22","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/S0140-6736(14)60958-2","volume":"384","author":"C Robert","year":"2014","unstructured":"Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384(9948):1109\u20131117","journal-title":"Lancet"},{"issue":"9","key":"4137_CR23","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1158\/2326-6066.CIR-17-0755","volume":"6","author":"FC Santini","year":"2018","unstructured":"Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M et al (2018) Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res 6(9):1093\u20131099","journal-title":"Cancer Immunol Res"},{"issue":"34","key":"4137_CR24","doi-asserted-by":"publisher","first-page":"3807","DOI":"10.1200\/JCO.2017.73.2289","volume":"35","author":"D Schadendorf","year":"2017","unstructured":"Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol 35(34):3807","journal-title":"J Clin Oncol"},{"issue":"2","key":"4137_CR25","doi-asserted-by":"publisher","first-page":"339","DOI":"10.4143\/crt.2020.790","volume":"53","author":"S-Q Tang","year":"2021","unstructured":"Tang S-Q, Tang L-L, Mao Y-P, Li W-F, Chen L, Zhang Y et al (2021) The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: a pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat 53(2):339\u2013354","journal-title":"Cancer Res Treat"},{"issue":"26","key":"4137_CR26","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","volume":"366","author":"SL Topalian","year":"2012","unstructured":"Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443\u20132454","journal-title":"N Engl J Med"},{"issue":"2","key":"4137_CR27","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1208\/s12248-021-00574-0","volume":"23","author":"JD Twomey","year":"2021","unstructured":"Twomey JD, Zhang B (2021) Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J 23(2):39","journal-title":"AAPS J"},{"issue":"7","key":"4137_CR28","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1200\/JCO.2015.66.1389","volume":"35","author":"JS Weber","year":"2017","unstructured":"Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35(7):785\u2013792","journal-title":"J Clin Oncol"},{"issue":"11","key":"4137_CR29","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1634\/theoncologist.2018-0686","volume":"24","author":"A Winer","year":"2019","unstructured":"Winer A, Ghatalia P, Bubes N, Anari F, Varshavsky A, Kasireddy V et al (2019) Dual checkpoint inhibition with ipilimumab plus nivolumab after progression on sequential PD-1\/PDL-1 inhibitors pembrolizumab and atezolizumab in a patient with Lynch syndrome, metastatic colon, and localized urothelial cancer. Oncologist 24(11):1416","journal-title":"Oncologist"},{"issue":"2","key":"4137_CR30","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1056\/NEJMoa1302369","volume":"369","author":"JD Wolchok","year":"2013","unstructured":"Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122\u2013133","journal-title":"N Engl J Med"},{"key":"4137_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.730320","volume":"12","author":"Q Zhao","year":"2021","unstructured":"Zhao Q, Zhang J, Xu L, Yang H, Liang N, Zhang L et al (2021) Safety and efficacy of the rechallenge of immune checkpoint inhibitors after immune-related adverse events in patients with cancer: a systemic review and meta-analysis. Front Immunol 12:730320","journal-title":"Front Immunol"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-022-04137-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-022-04137-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-022-04137-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T10:07:07Z","timestamp":1682417227000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-022-04137-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,21]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["4137"],"URL":"https:\/\/doi.org\/10.1007\/s00432-022-04137-4","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,21]]},"assertion":[{"value":"2 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This is an observational study retrospective study. An IRB official waiver of ethical approval was granted from the IRB of Lahey Hospital and Medical Center. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"No identifiable data was collected or being reported. No consent to participation is needed as approved by the Institutional Review Board.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"No identifiable data was collected or being reported. No consent to publish is needed as approved by the Institutional Review Board.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}