{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:12:42Z","timestamp":1790082762440,"version":"4.0.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T00:00:00Z","timestamp":1687132800000},"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><jats:title>Introduction<\/jats:title><jats:p>Immune checkpoint inhibitor (ICI) combination therapy has changed the treatment landscape for metastatic renal cell carcinoma (mRCC). However, little evidence exists on the treatment-related severe adverse events (SAEs) and fatal adverse events (FAEs) of ICI combination therapy in mRCC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We searched PubMed, Embase, and Cochrane Library databases to evaluate randomized controlled trials (RCTs) of ICI combination therapy versus conventional tyrosine kinase inhibitor (TKI)-targeted therapy in mRCC. Data on SAEs and FAEs were analyzed using revman5.4 software.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eight RCTs (n=5380) were identified. The analysis showed no differences in SAEs (60.5% vs. 64.5%) and FAEs (1.2% vs. 0.8%) between the ICI and TKI groups (odds ratio [OR], 0.83; 95%CI 0.58\u22121.19, p=0.300 and OR, 1.54; 95%CI 0.89\u22122.69, p=0.120, respectively). ICI-combination therapy was associated with less risk of hematotoxicities, including anemia (OR, 0.24, 95%CI 0.15\u20130.38, p&amp;lt;0.001), neutropenia (OR, 0.07, 95%CI 0.03\u20130.14, p&amp;lt;0.001), and thrombocytopenia (OR, 0.05, 95%CI 0.02\u22120.12, p&amp;lt;0.001), but with increased risks of hepatotoxicities (ALT increase [OR, 3.39, 95%CI 2.39\u20134.81, p&amp;lt;0.001] and AST increase [OR, 2.71, 95%CI 1.81\u22124.07, p&amp;lt;0.001]), gastrointestinal toxicities (amylase level increase [OR, 2.32, 95%CI 1.33\u20134.05, p=0.003] and decreased appetite [OR, 1.77, 95%CI 1.08\u20132.92, p=0.020]), endocrine toxicity (adrenal insufficiency [OR, 11.27, 95%CI 1.55\u201381.87, p=0.020]) and nephrotoxicity of proteinuria (OR, 2.21, 95%CI 1.06\u22124.61, p=0.030).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Compared with TKI, ICI combination therapy has less hematotoxicity in mRCC but more specific hepatotoxicity, gastrointestinal toxicity, endocrine toxicity, and nephrotoxicity, with a similar severe toxicity profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>, identifier CRD42023412669.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1196793","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T06:38:45Z","timestamp":1687156725000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Severe and fatal adverse events of immune checkpoint inhibitor combination therapy in patients with metastatic renal cell carcinoma: a systematic review and 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