{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T12:16:37Z","timestamp":1789820197056,"version":"4.0.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This systematic review and meta-analysis consolidates findings from recent randomized controlled trials (RCTs) on the efficacy of first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI-TKI) combination therapy for metastatic renal cell carcinoma (mRCC). We also explored prognostic biomarkers and clinical factors to inform treatment strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a systematic search of PubMed, Embase, the Cochrane Library, Web of Science, and major conference proceedings for RCTs published from January 2016 to December 2025. The inclusion criteria were: (1) treatment-na\u00efve patients with mRCC; (2) intervention with first-line ICI-TKI combination therapy; and (3) availability of extractable data for survival or safety endpoints. Effect estimates were aggregated using either a random-effects model (DerSimonian\u2013Laird) or a fixed-effects model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Six RCTs were included. The primary analysis of the overall population pooled data from five trials (N\u00a0=\u00a03,637), encompassing all risk groups defined by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Compared with control therapy, first-line ICI-TKI combination therapy significantly enhanced both progression-free survival (PFS), with a hazard ratio (HR) of 0.59 (95% confidence interval (CI) 0.51\u20130.67, P &amp;lt; 0.0001), and overall survival (OS), with an HR of 0.79 (95% CI 0.72\u20130.87, P &amp;lt; 0.0001). Efficacy varied by IMDC risk subgroup: favorable-risk patients exhibited a PFS benefit (HR 0.66, 95% CI 0.56\u20130.78, P &amp;lt; 0.0001) but no OS improvement (HR 0.96, 95% CI 0.79\u20131.18, P\u00a0=\u00a00.73); intermediate-risk patients had improved PFS (HR 0.60, 95% CI 0.53\u20130.69, P &amp;lt; 0.0001) and OS (HR 0.88, 95% CI 0.78\u20130.99, P\u00a0=\u00a00.03). Poor-risk patients derived the most substantial benefit, with improvements in both PFS (HR 0.50, 95% CI 0.41\u20130.61, P &amp;lt; 0.0001) and OS (HR 0.52, 95% CI 0.41\u20130.65, P &amp;lt; 0.0001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>First-line combination therapy with ICI-TKI significantly improves both PFS and OS in patients with mRCC. The magnitude of clinical benefit is positively associated with higher IMDC risk scores, with the most substantial improvements in both PFS and OS observed in patients with poor-risk disease. Collectively, these findings establish ICI-TKI combination therapy as the standard first-line treatment for patients with intermediate or poor-risk mRCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420251272113.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1805039","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T10:06:46Z","timestamp":1778839606000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy and safety of immune checkpoint inhibitors combined with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma: a risk-stratified systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingliang","family":"Rao","sequence":"first","affiliation":[{"name":"China-Japan Union Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinquan","family":"Gu","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiansong","family":"Han","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Ye","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14164059","article-title":"Epidemiology and prevention of renal cell carcinoma","volume":"14","author":"Makino","year":"2022","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1007\/s12032-018-1217-1","article-title":"Contemporary treatment of metastatic renal cell carcinoma","volume":"35","author":"Wiechno","year":"2018","journal-title":"Med Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2017-000185","article-title":"New treatment options for metastatic renal cell 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