{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T02:05:51Z","timestamp":1784340351272,"version":"3.55.0"},"reference-count":58,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.<\/jats:p>","DOI":"10.3390\/cancers14020302","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Marcus","family":"W\u00f6lffer","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6021-5837","authenticated-orcid":false,"given":"Florian","family":"Battke","sequence":"additional","affiliation":[{"name":"Center for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schulze","sequence":"additional","affiliation":[{"name":"Practice for Human Genetics, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Feldhahn","sequence":"additional","affiliation":[{"name":"Center for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Flatz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Martus","sequence":"additional","affiliation":[{"name":"Institute for Clinical Epidemiology and Applied Biostatistics (IKEaB), 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6185-4945","authenticated-orcid":false,"given":"Andrea","family":"Forschner","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3892\/ijo.2020.5088","article-title":"Cutaneous melanoma and the immunotherapy revolution (Review)","volume":"57","author":"Leonardi","year":"2020","journal-title":"Int. J. Oncol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1056\/NEJMoa1709030","article-title":"Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma","volume":"377","author":"Weber","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/s41591-018-0197-1","article-title":"Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma","volume":"24","author":"Amaria","year":"2018","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1001\/jamaoncol.2018.3923","article-title":"Fatal Toxic Effects Associated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis","volume":"4","author":"Wang","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.4110\/in.2020.20.e9","article-title":"Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors","volume":"20","author":"Choi","year":"2020","journal-title":"Immune Netw."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12967-018-1467-x","article-title":"Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade","volume":"16","author":"Valpione","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1001\/jamaoncol.2015.4368","article-title":"Ipilimumab Therapy in Patients with Advanced Melanoma and Preexisting Autoimmune Disorders","volume":"2","author":"Johnson","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jdermsci.2017.07.007","article-title":"Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab","volume":"88","author":"Fujisawa","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/jjco\/hyy201","article-title":"Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies","volume":"49","author":"Nakamura","year":"2019","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e000472","DOI":"10.1136\/esmoopen-2018-000472","article-title":"Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events","volume":"4","author":"Hoefsmit","year":"2019","journal-title":"ESMO Open"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/thy.2016.0345","article-title":"TSHR Gene Polymorphisms in the Enhancer Regions Are Most Strongly Associated with the Development of Graves\u2019 Disease, Especially Intractable Disease, and of Hashimoto\u2019s Disease","volume":"27","author":"Fujii","year":"2017","journal-title":"Thyroid"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.jaut.2015.07.009","article-title":"Immunogenetics of autoimmune thyroid diseases: A comprehensive review","volume":"64","author":"Lee","year":"2015","journal-title":"J. Autoimmun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e89569","DOI":"10.1172\/jci.insight.89569","article-title":"Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele","volume":"2","author":"Jang","year":"2017","journal-title":"JCI Insight"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/ng.468","article-title":"A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus","volume":"41","author":"Gateva","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, H., Ma, W., Yoneda, K.Y., Moore, E.H., Zhang, Y., Pu, L.L., Frampton, G.M., Molmen, M., Stephens, P.J., and Li, T. (2017). Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: A case report. J. Hematol. Oncol., 10.","DOI":"10.1186\/s13045-017-0433-z"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1016\/j.jid.2017.06.023","article-title":"HLA-A*26 Is Correlated with Response to Nivolumab in Japanese Melanoma Patients","volume":"137","author":"Ishida","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s40425-019-0659-0","article-title":"Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma\u2014Results of a prospective biomarker study","volume":"7","author":"Forschner","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_18","unstructured":"National Institutes of Health (NCI), Division of Cancer Treatment & Diagnosis, Cancer Therapy Evaluation Program (2017). Common Terminology Criteria for Adverse Events (CTCAE), Quick Reference. Version 5.0."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00281-018-0715-8","article-title":"Sex-related factors in autoimmune liver diseases","volume":"41","author":"Schwinge","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1111\/jgh.15041","article-title":"Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan","volume":"35","author":"Kitagataya","year":"2020","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40425-019-0502-7","article-title":"Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury","volume":"7","author":"Tang","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00535-018-1440-8","article-title":"Clinical and pathophysiological aspects of type 1 autoimmune pancreatitis","volume":"53","author":"Uchida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1093\/rheumatology\/key397","article-title":"Sex disparities in clinical characteristics and prognosis of immunoglobulin G4-related disease: A prospective study of 403 patients","volume":"58","author":"Wang","year":"2019","journal-title":"Rheumatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8862","DOI":"10.1111\/jcmm.15540","article-title":"Impact of diet and genes on murine autoimmune pancreatitis","volume":"24","author":"Jaster","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1053\/j.gastro.2013.01.068","article-title":"The epidemiology of pancreatitis and pancreatic cancer","volume":"144","author":"Yadav","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1200\/JCO.18.01998","article-title":"Evaluation of Two Dosing Regimens for Nivolumab in Combination with Ipilimumab in Patients with Advanced Melanoma: Results from the Phase IIIb\/IV CheckMate 511 Trial","volume":"37","author":"Meyer","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/S1470-2045(19)30151-2","article-title":"Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): A multicentre, phase 2, randomised, controlled trial","volume":"20","author":"Rozeman","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"406","DOI":"10.2340\/00015555-2872","article-title":"Blood Predictive Biomarkers for Nivolumab in Advanced Melanoma","volume":"98","author":"Chasseuil","year":"2018","journal-title":"Acta Derm. Venereol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1001\/jamaoncol.2019.5570","article-title":"Association between Immune-Related Adverse Events and Recurrence-Free Survival among Patients with Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial","volume":"6","author":"Eggermont","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e403","DOI":"10.3747\/co.25.4047","article-title":"Predictors of immunotherapy-induced immune-related adverse events","volume":"25","author":"Kartolo","year":"2018","journal-title":"Curr. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/annonc\/mdw443","article-title":"Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab","volume":"28","author":"Menzies","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Abd El Aziz, M.A., Facciorusso, A., Nayfeh, T., Saadi, S., Elnaggar, M., Cotsoglou, C., and Sacco, R. (2020). Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma. Vaccines, 8.","DOI":"10.3390\/vaccines8040616"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/apt.16217","article-title":"Systematic review with meta-analysis: Safety and tolerability of immune checkpoint inhibitors in patients with pre-existing inflammatory bowel diseases","volume":"53","author":"Meserve","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121","DOI":"10.7326\/M17-2073","article-title":"Use of Immune Checkpoint Inhibitors in the Treatment of Patients with Cancer and Preexisting Autoimmune Disease: A Systematic Review","volume":"168","author":"Shah","year":"2018","journal-title":"Ann. Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1073\/pnas.1525001113","article-title":"Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo","volume":"113","author":"Hayashi","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1038\/s41591-019-0639-4","article-title":"Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy","volume":"25","author":"Chowell","year":"2019","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1158\/2326-6066.CIR-17-0491","article-title":"Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells","volume":"6","author":"Wang","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/s41379-020-0499-y","article-title":"DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: Proposal of an algorithmic approach","volume":"33","author":"Alomari","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s10637-019-00845-w","article-title":"Germinal Immunogenetics predict treatment outcome for PD-1\/PD-L1 checkpoint inhibitors","volume":"38","author":"Refae","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17067","DOI":"10.1038\/s41598-019-53633-0","article-title":"IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice","volume":"9","author":"Yoshizaki","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3109\/08916934.2013.866101","article-title":"Polymorphisms in TSHR and IL1RN genes and the risk and prognosis of Hashimoto\u2019s thyroiditis","volume":"47","author":"Zaaber","year":"2014","journal-title":"Autoimmunity"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/dmrr.2552","article-title":"PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile","volume":"30","author":"Pizarro","year":"2014","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1093\/rheumatology\/ker211","article-title":"Effects of genetic polymorphisms of programmed cell death 1 and its ligands on the development of ankylosing spondylitis","volume":"50","author":"Huang","year":"2011","journal-title":"Rheumatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1210\/jc.2009-1404","article-title":"Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison\u2019s disease and Graves\u2019 disease susceptibility","volume":"94","author":"Mitchell","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12026-015-8694-5","article-title":"Immunological function of Blimp-1 in dendritic cells and relevance to autoimmune diseases","volume":"63","author":"Kim","year":"2015","journal-title":"Immunol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.4049\/jimmunol.1600941","article-title":"Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity","volume":"199","author":"Roberts","year":"2017","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/leu.2016.243","article-title":"Loss of PRDM1\/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma","volume":"31","author":"Xia","year":"2017","journal-title":"Leukemia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.humpath.2017.06.012","article-title":"PD-L1 and immune escape: Insights from melanoma and other lineage-unrelated malignancies","volume":"66","author":"Frydenlund","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4044","DOI":"10.2174\/1381612825666181219163534","article-title":"Association of SLCO1B1 Polymorphisms and Atorvastatin Safety and Efficacy: A Meta-analysis","volume":"24","author":"Du","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.2217\/pgs-2016-0063","article-title":"Polymorphisms in SLCO1B1 and UGT1A1 are associated with sorafenib-induced toxicity","volume":"17","author":"Bins","year":"2016","journal-title":"Pharmacogenomics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/bcpt.13284","article-title":"Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole-induced liver injury","volume":"125","author":"Jin","year":"2019","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1126\/science.1258973","article-title":"DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1","volume":"346","author":"Wang","year":"2014","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1093\/hmg\/ddy375","article-title":"FAN1 modifies Huntington\u2019s disease progression by stabilizing the expanded HTT CAG repeat","volume":"28","author":"Goold","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11060-019-03273-1","article-title":"Neurological and related adverse events in immune checkpoint inhibitors: A pharmacovigilance study from the Japanese Adverse Drug Event Report database","volume":"145","author":"Sato","year":"2019","journal-title":"J. Neurooncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1634\/theoncologist.2018-0359","article-title":"Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Neurologic Toxicity: Illustrative Case and Review of the Literature","volume":"24","author":"Reynolds","year":"2019","journal-title":"Oncologist"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1200\/JCO.2017.73.2289","article-title":"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","volume":"35","author":"Schadendorf","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/CCO.0000000000000709","article-title":"Triplet combination of BRAF, MEK and PD-1\/PD-L1 blockade in melanoma: The more the better?","volume":"33","author":"Trojaniello","year":"2021","journal-title":"Curr. Opin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/2\/302\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:01:43Z","timestamp":1760364103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/2\/302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,8]]},"references-count":58,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cancers14020302"],"URL":"https:\/\/doi.org\/10.3390\/cancers14020302","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,8]]}}}