{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:18:18Z","timestamp":1787735898802,"version":"build-2784847793"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004770","name":"Universit\u00e0 degli Studi di Parma","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004770","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Metastasis Rev"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Immune checkpoint inhibitor (ICI)\u2013based combinations represent the standard first-line treatment for metastatic clear cell renal cell carcinoma (mRCC), although robust biomarkers for treatment selection remain undefined. We conducted a systematic review to identify biomarkers assessed in randomized clinical trials (RCTs) on first-line ICI-based regimens. Following PRISMA guidelines, we searched PubMed, Web of Science and Scopus (January 2018\u2013October 2025) for phase III RCTs investigating first-line ICI-based therapies in mRCC with molecular or circulating biomarker analyses. Given heterogeneity across studies, a qualitative synthesis was performed. Sixteen reports were included. Biomarkers were assessed using immunohistochemistry, transcriptomics, genomic sequencing and blood analyses. PD-L1 expression did not reliably discriminate benefit across ICI-based combinations, although it revealed a negative prognostic influence with sunitinib and a potential predictive role for nivolumab-ipilimumab. Tumours with angiogenic signatures were consistently associated with improved outcomes, suggesting prognostic relevance, while derived limited additional benefit from ICIs. Immune-related signatures were associated with ICI response, whereas proliferation and\n                    <jats:italic>MYC<\/jats:italic>\n                    -related signatures identified disease with poor prognosis across treatments. Individual mutations (e.g.\n                    <jats:italic>PBRM1<\/jats:italic>\n                    ,\n                    <jats:italic>VHL<\/jats:italic>\n                    ,\n                    <jats:italic>BAP1<\/jats:italic>\n                    ,\n                    <jats:italic>PTEN<\/jats:italic>\n                    ) showed heterogeneous and mainly prognostic associations, whereas composite gene panels (e.g. rDM) may offer better predictive value. Circulating biomarkers, including inflammatory cytokines and KIM-1 dynamics, demonstrated promising prognostic and early predictive signals. No validated biomarker currently supports treatment selection among first-line ICI-based combinations in mRCC. Future research should prioritize adaptive, biomarker-guided trial designs integrating longitudinal multi-omic profiling and circulating biomarkers to generate clinical evidence and support personalized treatments.\n                  <\/jats:p>","DOI":"10.1007\/s10555-026-10371-w","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:28:50Z","timestamp":1787732930000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular biomarkers in metastatic clear cell renal cell carcinoma treated with first-line immune combinations: a systematic review of phase III randomized clinical trials by Meet-URO group"],"prefix":"10.1007","volume":"45","author":[{"given":"Anna Amela","family":"Valsecchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Maffezzoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Concetta","family":"Cursano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Di Costanzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Malgeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia Alberto","family":"Di Civita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigida","family":"Maiorano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Messina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Procopio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Bimbatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0876-0226","authenticated-orcid":false,"given":"Sebastiano","family":"Buti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Elena","family":"Rebuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Di Maio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"issue":"8","key":"10371_CR1","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.annonc.2024.05.537","volume":"35","author":"T Powles","year":"2024","unstructured":"Powles, T., Albiges, L., Bex, A., et al. (2024). Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology, 35(8), 692\u2013706. https:\/\/doi.org\/10.1016\/j.annonc.2024.05.537","journal-title":"Annals of Oncology"},{"issue":"5","key":"10371_CR2","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/nrurol.2010.47","volume":"7","author":"WM Linehan","year":"2010","unstructured":"Linehan, W. M., Srinivasan, R., & Schmidt, L. S. (2010). The genetic basis of kidney cancer: A metabolic disease. Nature Reviews Urology, 7(5), 277\u2013285. https:\/\/doi.org\/10.1038\/nrurol.2010.47","journal-title":"Nature Reviews Urology"},{"issue":"11","key":"10371_CR3","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41585-024-00876-w","volume":"21","author":"C Liao","year":"2024","unstructured":"Liao, C., Hu, L., & Zhang, Q. (2024). Von Hippel-Lindau protein signalling in clear cell renal cell carcinoma. Nature Reviews Urology, 21(11), 662\u2013675. https:\/\/doi.org\/10.1038\/s41585-024-00876-w","journal-title":"Nature Reviews Urology"},{"issue":"7331","key":"10371_CR4","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/nature09639","volume":"469","author":"I Varela","year":"2011","unstructured":"Varela, I., Tarpey, P., Raine, K., et al. (2011). Exome sequencing identifies frequent mutation of the SWI\/SNF complex gene PBRM1 in renal carcinoma. Nature, 469(7331), 539\u2013542. https:\/\/doi.org\/10.1038\/nature09639","journal-title":"Nature"},{"issue":"1","key":"10371_CR5","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s12894-024-01559-9","volume":"24","author":"Q Zhao","year":"2024","unstructured":"Zhao, Q., Hong, B., Zhang, X., Xue, J., Guo, S., & Zhang, N. (2024). Frequent gene mutations and the correlations with clinicopathological features in clear cell renal cell carcinoma: Preliminary study based on Chinese population and TCGA database. BMC Urology, 24(1), 170. https:\/\/doi.org\/10.1186\/s12894-024-01559-9","journal-title":"BMC Urology"},{"key":"10371_CR6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12010016","author":"L Carril-Ajuria","year":"2019","unstructured":"Carril-Ajuria, L., Santos, M., Rold\u00e1n-Romero, J. M., Rodriguez-Antona, C., & de Velasco, G. (2019). Prognostic and predictive value of PBRM1 in clear cell renal cell carcinoma. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers12010016","journal-title":"Cancers (Basel)"},{"issue":"3","key":"10371_CR7","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.jncc.2022.07.001","volume":"2","author":"W Xu","year":"2022","unstructured":"Xu, W., Anwaier, A., Liu, W., et al. (2022). The unique genomic landscape and prognostic mutational signature of Chinese clear cell renal cell carcinoma. Journal of the National Cancer Center, 2(3), 162\u2013170. https:\/\/doi.org\/10.1016\/j.jncc.2022.07.001","journal-title":"Journal of the National Cancer Center"},{"issue":"2","key":"10371_CR8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/s1470-2045(12)70559-4","volume":"14","author":"DY Heng","year":"2013","unstructured":"Heng, D. Y., Xie, W., Regan, M. M., et al. (2013). External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncology, 14(2), 141\u2013148. https:\/\/doi.org\/10.1016\/s1470-2045(12)70559-4","journal-title":"Lancet Oncology"},{"issue":"16_suppl","key":"10371_CR9","doi-asserted-by":"publisher","first-page":"e16543","DOI":"10.1200\/JCO.2023.41.16_suppl.e16543","volume":"41","author":"LJ Centeno","year":"2023","unstructured":"Centeno, L. J., Pan, H., Malik, P., et al. (2023). Genome sequencing-based prognosis, mutational analysis, and survival rate of clear cell renal cell carcinoma. Journal of Clinical Oncology, 41(16_suppl), e16543\u2013e16543. https:\/\/doi.org\/10.1200\/JCO.2023.41.16_suppl.e16543","journal-title":"Journal of Clinical Oncology"},{"key":"10371_CR10","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004316","author":"RJ Motzer","year":"2022","unstructured":"Motzer, R. J., Choueiri, T. K., McDermott, D. F., et al. (2022). Biomarker analysis from CheckMate 214: Nivolumab plus ipilimumab versus sunitinib in renal cell carcinoma. Journal for Immunotherapy of Cancer. https:\/\/doi.org\/10.1136\/jitc-2021-004316","journal-title":"Journal for Immunotherapy of Cancer"},{"issue":"11","key":"10371_CR11","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1038\/s41591-020-1044-8","volume":"26","author":"RJ Motzer","year":"2020","unstructured":"Motzer, R. J., Robbins, P. B., Powles, T., et al. (2020). Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: Biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nature Medicine, 26(11), 1733\u20131741. https:\/\/doi.org\/10.1038\/s41591-020-1044-8","journal-title":"Nature Medicine"},{"issue":"16_suppl","key":"10371_CR12","doi-asserted-by":"publisher","first-page":"4505","DOI":"10.1200\/JCO.2024.42.16_suppl.4505","volume":"42","author":"BI Rini","year":"2024","unstructured":"Rini, B. I., Plimack, E. R., Stus, V., et al. (2024). Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC). Journal of Clinical Oncology, 42(16_suppl), 4505\u20134505. https:\/\/doi.org\/10.1200\/JCO.2024.42.16_suppl.4505","journal-title":"Journal of Clinical Oncology"},{"issue":"4","key":"10371_CR13","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.annonc.2024.12.003","volume":"36","author":"RJ Motzer","year":"2025","unstructured":"Motzer, R. J., Porta, C., Eto, M., et al. (2025). Biomarker analyses from the phase III randomized CLEAR trial: Lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma. Annals of Oncology, 36(4), 375\u2013386. https:\/\/doi.org\/10.1016\/j.annonc.2024.12.003","journal-title":"Annals of Oncology"},{"issue":"6_suppl","key":"10371_CR14","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1200\/JCO.2023.41.6_suppl.608","volume":"41","author":"TK Choueiri","year":"2023","unstructured":"Choueiri, T. K., Motzer, R. J., Powles, T., et al. (2023). Biomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma (aRCC). Journal of Clinical Oncology, 41(6_suppl), 608\u2013608. https:\/\/doi.org\/10.1200\/JCO.2023.41.6_suppl.608","journal-title":"Journal of Clinical Oncology"},{"issue":"19","key":"10371_CR15","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1056\/NEJMoa2212851","volume":"388","author":"TK Choueiri","year":"2023","unstructured":"Choueiri, T. K., Powles, T., Albiges, L., et al. (2023). Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. New England Journal of Medicine, 388(19), 1767\u20131778. https:\/\/doi.org\/10.1056\/NEJMoa2212851","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"10371_CR16","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/s1470-2045(25)00343-2","volume":"26","author":"A Zhou","year":"2025","unstructured":"Zhou, A., Shen, P., Li, J., et al. (2025). First-line benmelstobart plus anlotinib versus sunitinib in advanced renal cell carcinoma (ETER100): A multicentre, randomized, open-label, phase 3 trial. Lancet Oncology, 26(9), 1145\u20131157. https:\/\/doi.org\/10.1016\/s1470-2045(25)00343-2","journal-title":"Lancet Oncology"},{"issue":"10189","key":"10371_CR17","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1016\/s0140-6736(19)30723-8","volume":"393","author":"BI Rini","year":"2019","unstructured":"Rini, B. I., Powles, T., Atkins, M. B., et al. (2019). Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomized controlled trial. Lancet, 393(10189), 2404\u20132415. https:\/\/doi.org\/10.1016\/s0140-6736(19)30723-8","journal-title":"Lancet"},{"issue":"2","key":"10371_CR18","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1001\/jamaoncol.2021.5981","volume":"8","author":"RJ Motzer","year":"2022","unstructured":"Motzer, R. J., Powles, T., Atkins, M. B., et al. (2022). Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncology, 8(2), 275\u2013280. https:\/\/doi.org\/10.1001\/jamaoncol.2021.5981","journal-title":"JAMA Oncology"},{"issue":"10","key":"10371_CR19","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/s1470-2045(19)30413-9","volume":"20","author":"RJ Motzer","year":"2019","unstructured":"Motzer, R. J., Rini, B. I., McDermott, D. F., et al. (2019). Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncology, 20(10), 1370\u20131385. https:\/\/doi.org\/10.1016\/s1470-2045(19)30413-9","journal-title":"Lancet Oncology"},{"key":"10371_CR20","unstructured":"ESMO. (2025). Discussant: Lymphocyte Activation Gene-3 (LAG3) Expression patterns KIM-K-L, and biomarkers of response to first-line nivolumab plus ipilimumab therapy\u201d available at https:\/\/www.urotoday.com\/conference-highlights\/esmo-2025\/esmo-2025-kidney-cancer\/164107-esmo-2025-discussant-lymphocyte-activation-gene-3-lag3-expression-patterns-kidney-injury-molecule-1-kim-1-levels-and-biomarkers-of-response-to-first-line-nivolumab-plus-ipilimumab-therapy.html Accessed 19 February 2026"},{"issue":"10","key":"10371_CR21","doi-asserted-by":"publisher","first-page":"3475","DOI":"10.1038\/s41591-025-03867-5","volume":"31","author":"BI Rini","year":"2025","unstructured":"Rini, B. I., Plimack, E. R., Stus, V., et al. (2025). Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nature Medicine, 31(10), 3475\u20133484. https:\/\/doi.org\/10.1038\/s41591-025-03867-5","journal-title":"Nature Medicine"},{"key":"10371_CR22","doi-asserted-by":"publisher","unstructured":"McDermott, D. F., Huseni, M. A., Atkins, M. B., et al. (2018). Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nature Medicine, 24(6), 749\u2013757. https:\/\/doi.org\/10.1038\/s41591-018-0053-3","DOI":"10.1038\/s41591-018-0053-3"},{"issue":"6","key":"10371_CR23","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.ccell.2020.10.011","volume":"38","author":"RJ Motzer","year":"2020","unstructured":"Motzer, R. J., Banchereau, R., Hamidi, H., et al. (2020). Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell, 38(6), 803-817.e4. https:\/\/doi.org\/10.1016\/j.ccell.2020.10.011","journal-title":"Cancer Cell"},{"issue":"6375","key":"10371_CR24","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1126\/science.aao4572","volume":"359","author":"D Chowell","year":"2018","unstructured":"Chowell, D., Morris, L. G. T., Grigg, C. M., et al. (2018). Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science, 359(6375), 582\u2013587. https:\/\/doi.org\/10.1126\/science.aao4572","journal-title":"Science"},{"issue":"5","key":"10371_CR25","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.ccell.2024.03.002","volume":"42","author":"RM Saliby","year":"2024","unstructured":"Saliby, R. M., Labaki, C., Jammihal, T. R., et al. (2024). Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes. Cancer Cell, 42(5), 732\u2013735. https:\/\/doi.org\/10.1016\/j.ccell.2024.03.002","journal-title":"Cancer Cell"},{"issue":"8","key":"10371_CR26","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1158\/1078-0432.Ccr-21-3329","volume":"28","author":"R Cristescu","year":"2022","unstructured":"Cristescu, R., Nebozhyn, M., Zhang, C., et al. (2022). Transcriptomic determinants of response to pembrolizumab monotherapy across solid tumor types. Clinical Cancer Research, 28(8), 1680\u20131689. https:\/\/doi.org\/10.1158\/1078-0432.Ccr-21-3329","journal-title":"Clinical Cancer Research"},{"issue":"3","key":"10371_CR27","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1158\/2159-8290.Cd-23-0680","volume":"14","author":"TK Choueiri","year":"2024","unstructured":"Choueiri, T. K., Donahue, A. C., Braun, D. A., et al. (2024). Integrative analyses of tumor and peripheral biomarkers in the treatment of advanced renal cell carcinoma. Cancer Discovery, 14(3), 406\u2013423. https:\/\/doi.org\/10.1158\/2159-8290.Cd-23-0680","journal-title":"Cancer Discovery"},{"issue":"5_suppl","key":"10371_CR28","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1200\/JCO.2025.43.5_suppl.437","volume":"43","author":"W Xu","year":"2025","unstructured":"Xu, W., Vemula, S. V., Motzer, R. J., et al. (2025). Evaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC): Post-hoc analysis of CheckMate 214. Journal of Clinical Oncology, 43(5_suppl), 437\u2013437. https:\/\/doi.org\/10.1200\/JCO.2025.43.5_suppl.437","journal-title":"Journal of Clinical Oncology"},{"key":"10371_CR29","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1200\/JCO.2025.43.5_suppl.594","volume":"43","author":"M Machaalani","year":"2025","unstructured":"Machaalani, M., Saliby, R. M., Zhong, C., et al. (2025). KIM-1 as a circulating biomarker in metastatic RCC: Post-hoc analysis of JAVELIN Renal 101. Journal of Clinical Oncology, 43, 594\u2013594. https:\/\/doi.org\/10.1200\/JCO.2025.43.5_suppl.594","journal-title":"Journal of Clinical Oncology"},{"issue":"4","key":"10371_CR30","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.eururo.2021.12.010","volume":"81","author":"TO Bui","year":"2022","unstructured":"Bui, T. O., Dao, V. T., Nguyen, V. T., Feugeas, J. P., Pamoukdjian, F., & Bousquet, G. (2022). Genomics of clear-cell renal cell carcinoma: A systematic review and meta-analysis. European Urology, 81(4), 349\u2013361. https:\/\/doi.org\/10.1016\/j.eururo.2021.12.010","journal-title":"European Urology"},{"key":"10371_CR31","doi-asserted-by":"publisher","unstructured":"Quhal, F., Mori, K., Bruchbacher, A., et al. (2021). First-line immunotherapy-based combinations for metastatic renal cell carcinoma: A systematic review and network meta-analysis. Eur Urol Oncol. 4(5),755\u2013765. https:\/\/doi.org\/10.1016\/j.euo.2021.03.001","DOI":"10.1016\/j.euo.2021.03.001"},{"issue":"5","key":"10371_CR32","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrclinonc.2018.29","volume":"15","author":"D Fukumura","year":"2018","unstructured":"Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., & Jain, R. K. (2018). Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges. Nature Reviews Clinical Oncology, 15(5), 325\u2013340. https:\/\/doi.org\/10.1038\/nrclinonc.2018.29","journal-title":"Nature Reviews Clinical Oncology"},{"issue":"13","key":"10371_CR33","first-page":"5132","volume":"61","author":"O Nakano","year":"2001","unstructured":"Nakano, O., Sato, M., Naito, Y., et al. (2001). Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: Clinicopathologic demonstration of antitumor immunity. Cancer Research, 61(13), 5132\u20135136.","journal-title":"Cancer Research"},{"issue":"5","key":"10371_CR34","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.eururo.2021.01.003","volume":"79","author":"T Powles","year":"2021","unstructured":"Powles, T., Atkins, M. B., Escudier, B., et al. (2021). Efficacy and safety of atezolizumab plus bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with metastatic renal cell carcinoma in IMmotion150: A randomized phase 2 clinical trial. European Urology, 79(5), 665\u2013673. https:\/\/doi.org\/10.1016\/j.eururo.2021.01.003","journal-title":"European Urology"},{"key":"10371_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2025.09.4169","author":"R Flippot","year":"2025","unstructured":"Flippot, R., Vano, Y. A., Dalban, C., et al. (2025). Nivolumab in metastatic clear-cell renal cell carcinoma: An integrative biomarker analysis from the NIVOREN GETUG-AFU 26 phase 2 study. European Urology. https:\/\/doi.org\/10.1016\/j.eururo.2025.09.4169","journal-title":"European Urology"},{"issue":"18","key":"10371_CR36","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.1158\/1078-0432.CCR-22-0923","volume":"28","author":"T Denize","year":"2022","unstructured":"Denize, T., Hou, Y., Pignon, J. C., et al. (2022). Transcriptomic correlates of tumor cell PD-L1 expression and response to nivolumab monotherapy in metastatic clear cell renal cell carcinoma. Clinical Cancer Research, 28(18), 4045\u20134055. https:\/\/doi.org\/10.1158\/1078-0432.CCR-22-0923","journal-title":"Clinical Cancer Research"},{"key":"10371_CR37","doi-asserted-by":"publisher","first-page":"5023","DOI":"10.1200\/JCO.2020.38.15_suppl.5023","volume":"38","author":"M Ficial","year":"2020","unstructured":"Ficial, M., Jegede, O., Sant\u2019Angelo, M., et al. (2020). Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial. Journal of Clinical Oncology, 38, 5023\u20135023. https:\/\/doi.org\/10.1200\/JCO.2020.38.15_suppl.5023","journal-title":"Journal of Clinical Oncology"},{"issue":"5","key":"10371_CR38","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/s1470-2045(22)00128-0","volume":"23","author":"YA Vano","year":"2022","unstructured":"Vano, Y. A., Elaidi, R., Bennamoun, M., et al. (2022). Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): A biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncology, 23(5), 612\u2013624. https:\/\/doi.org\/10.1016\/s1470-2045(22)00128-0","journal-title":"Lancet Oncology"},{"key":"10371_CR39","unstructured":"2591O Efficacy of cabozantinib and nivolumab in cluster 1\/2 metastatic clear cell renal cell carcinoma: Results from OPTIC RCC apItoanR-bb, Haake SMea, Annals of Oncology V, S1298."},{"key":"10371_CR40","doi-asserted-by":"publisher","first-page":"S281","DOI":"10.1016\/j.annonc.2025.08.659","volume":"36","author":"GC Giudice","year":"2025","unstructured":"Giudice, G. C., Maffezzoli, M., Mazzaschi, G., et al. (2025). 228eP ABCA1 and ABCG1 cholesterol transporters expression on metastatic renal cell carcinoma, blood cholesterol and triglycerides, CONUT score: Impact on immunotherapy outcomes (CHOMET study). Annals of Oncology, 36, S281. https:\/\/doi.org\/10.1016\/j.annonc.2025.08.659","journal-title":"Annals of Oncology"},{"issue":"4","key":"10371_CR41","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1016\/j.cell.2019.10.007","volume":"179","author":"DJ Clark","year":"2019","unstructured":"Clark, D. J., Dhanasekaran, S. M., Petralia, F., et al. (2019). Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell, 179(4), 964-983.e31. https:\/\/doi.org\/10.1016\/j.cell.2019.10.007","journal-title":"Cell"},{"issue":"6","key":"10371_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2022.100634","volume":"7","author":"SE Rebuzzi","year":"2022","unstructured":"Rebuzzi, S. E., Signori, A., Buti, S., et al. (Dec2022). Validation of the Meet-URO score in patients with metastatic renal cell carcinoma receiving first-line nivolumab and ipilimumab in the Italian Expanded Access Program. ESMO Open., 7(6), Article 100634. https:\/\/doi.org\/10.1016\/j.esmoop.2022.100634","journal-title":"ESMO Open."},{"issue":"Suppl 2","key":"10371_CR43","doi-asserted-by":"publisher","first-page":"S1300","DOI":"10.1016\/j.annonc.2025.08.3210","volume":"36","author":"W Xu","year":"2025","unstructured":"Xu, W., Choueiri, T. K., Powles, T., et al. (2025). 2594MO Association of circulating kidney injury molecule-1 (KIM-1) levels with clinical outcomes in advanced renal cell carcinoma (aRCC): Retrospective analysis of COSMIC-313. Annals of Oncology, 36(Suppl 2), S1300\u2013S1301.","journal-title":"Annals of Oncology"},{"issue":"12","key":"10371_CR44","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1016\/j.annonc.2025.08.007","volume":"36","author":"BI Rini","year":"2025","unstructured":"Rini, B. I., Albiges, L., Tang, X., Koeppen, H., Bex, A., Su\u00e1rez, C., et al. (2025). Circulating kidney injury molecule-1 (KIM-1) and association with outcome to adjuvant immunotherapy in renal cell carcinoma. Annals of Oncology, 36(12), 1525\u20131534. https:\/\/doi.org\/10.1016\/j.annonc.2025.08.007","journal-title":"Annals of Oncology"},{"key":"10371_CR45","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/s41416-025-02985-8","volume":"133","author":"T Kato","year":"2025","unstructured":"Kato, T., Shiota, M., Nishimoto, K., Matsubara, N., Osawa, T., Abe, T., et al. (2025). Prognostic significance of circulating tumor DNA alterations in advanced renal cell carcinoma from SCRUM-Japan MONSTAR-SCREEN: A nationwide genomic profiling project. British Journal of Cancer, 133, 111\u2013120. https:\/\/doi.org\/10.1038\/s41416-025-02985-8","journal-title":"British Journal of Cancer"},{"issue":"16_suppl","key":"10371_CR46","doi-asserted-by":"publisher","first-page":"4502","DOI":"10.1200\/JCO.2026.44.16_suppl.4502","volume":"44","author":"TK Choueiri","year":"2026","unstructured":"Choueiri, T. K., Tomczak, P., Haas, N. B., et al. (2026). CtDNA analysis in participants with renal cell carcinoma treated with adjuvant pembrolizumab or placebo in the KEYNOTE-564 trial. Journal of Clinical Oncology, 44(16_suppl), 4502. https:\/\/doi.org\/10.1200\/JCO.2026.44.16_suppl.4502","journal-title":"Journal of Clinical Oncology"},{"key":"10371_CR47","doi-asserted-by":"publisher","unstructured":"Duan, X.P., Qin, B.D., Jiao, X.D., Liu, K., Wang, Z., & Zang, Y.S.\u00a0 (2024). New clinical trial design in precision medicine: Discovery, development and direction.\u00a0Signal Transduct Target Ther. 9(1):57. Published 2024 Mar 4. https:\/\/doi.org\/10.1038\/s41392-024-01760-0","DOI":"10.1038\/s41392-024-01760-0"},{"issue":"1","key":"10371_CR48","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41591-022-02160-z","volume":"29","author":"V Subbiah","year":"2023","unstructured":"Subbiah, V. (2023). The next generation of evidence-based medicine. Nature Medicine, 29(1), 49\u201358. https:\/\/doi.org\/10.1038\/s41591-022-02160-z","journal-title":"Nature Medicine"},{"key":"10371_CR49","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.euros.2022.11.006","volume":"47","author":"I Ouzaid","year":"2023","unstructured":"Ouzaid, I., Rioux-Leclercq, N., Khene, Z. E., Bensalah, K., & Kammerer-Jacquet, S. F. (2023). Can molecular classifications help tailor first-line treatment of metastatic renal cell carcinoma? A systematic review of available models. European Urology Open Science, 47, 12\u201319. https:\/\/doi.org\/10.1016\/j.euros.2022.11.006","journal-title":"European Urology Open Science"}],"container-title":["Cancer and Metastasis Reviews"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10555-026-10371-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10555-026-10371-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10555-026-10371-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:28:53Z","timestamp":1787732933000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10555-026-10371-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["10371"],"URL":"https:\/\/doi.org\/10.1007\/s10555-026-10371-w","relation":{},"ISSN":["1573-7233"],"issn-type":[{"value":"1573-7233","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"2 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"\u00a0The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"64"}}