{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:21:17Z","timestamp":1790108477332,"version":"4.0.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"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. Oncol."],"abstract":"<jats:p>The combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) can be associated with significant toxicity. We performed a systematic review and meta-analysis of the toxicity of combination treatment of ICIs with TKIs (ICI + TKI) in clinical trials with solid organ malignancies. Our primary endpoint explored the incidence of grade 3 - 5 (G3-5) treatment-related toxicity and our secondary endpoints included the incidence of toxicity by treatment type, disease type and studies with run-in strategies. A total of 9750 abstracts were identified, of which 72 eligible studies were included. The most common disease types were non-small cell lung cancer (n=8, 11.1%), renal cell carcinoma (n=10, 13.8%) and hepatobiliary cancers (n=10, 13.8%). The overall incidence of G3-5 toxicity was 56% (95% CI = 50% \u2013 61%). The most common TKIs combined with ICIs in this analysis were multi-targeted TKIs (n = 52, 72%), VEGF specific (n = 9, 12.5%), or oncogene-targeting TKIs (<jats:italic>EGFR, ALK, BRAF, MEK<\/jats:italic>) (n =11, 15.3%). Oncogene-targeted TKIs were associated a higher incidence of rashes and immune related adverse events (irAEs) and lower incidence of hypertension. In studies which used a TKI \u2018run-in\u2019 to mitigate toxicity, the pooled estimate of G3-5 toxicity was 71% (95% CI 57-81%). Almost half of studies (48%) omitted the incidence of G3-5 irAEs. Our work suggests that the majority of patients who receive ICI-TKI combinations will experience high grade toxicity (G3-G5) and that toxicity may be specific to TKI partner (Oncogene targeted TKIs: Rash, irAEs; VEGF\/Multitargeted: Hypertension). These data did not suggest that a TKI \u2018run-in\u2019 was associated with a lower incidence of G3-5 toxicity. Reporting of irAEs was inconsistent supporting the need for harmonisation of adverse event reporting to include onset, duration and treatment.<\/jats:p><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:uri>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:uri>, identifier CRD42022367416.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1380453","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T04:37:49Z","timestamp":1721018269000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Toxicity of immune checkpoint inhibitors and tyrosine kinase inhibitor combinations in solid tumours: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"14","author":[{"given":"David","family":"O\u2019Reilly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline 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