Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Centre for Cancer Translational and Clinical Research Institute Newcastle University Newcastle Upon Tyne UK

Department of Diagnostic and Public Health Section of Pathology University of Verona Verona Italy

Department of Internal Medicine and Medical Specialties University of Genova Genoa Italy

Department of Medical Oncology IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Department of Medicine and Surgery Section of Radiology University of Parma Parma Italy

Department of Medicine and Surgery University of Parma Parma Italy

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

Department of Oncology Oncology Unit Istituto Oncologico Veneto IOV IRCCS Padua Italy

Department of Oncology Portsmouth Hospitals University NHS Trust Portsmouth UK

Faculty of Science and Health School of Pharmacy and Biomedical Sciences University of Portsmouth Portsmouth UK

Medical Oncology Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

Medical Oncology Ospedale Santa Corona 17027 Pietra Ligure Italy

Medical Oncology Unit 1 IRCCS Ospedale Policlinico San Martino Genoa Italy

Medical Oncology Unit Ospedale San Paolo Savona Italy

Medical Oncology Unit University Hospital of Parma Via Gramsci 14 43126 Parma Italy

Oncology Unit Macerata Hospital 62100 Macerata Italy

Pathology Unit University Hospital of Parma Parma Italy

Section of biostatistics Department of Health Sciences University of Genova Genoa Italy

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Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–1127. doi: 10.1056/NEJMoa1816714. PubMed DOI

Motzer R, Alekseev B, Rha SY, et al. lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289–1300. doi: 10.1056/NEJMoa2035716. PubMed DOI

Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31(8):1030–1039. doi: 10.1016/j.annonc.2020.04.010. PubMed DOI PMC

Choueiri TK, Powles T, Burotto M, et al. nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829–841. doi: 10.1056/NEJMoa2026982. PubMed DOI PMC

Motzer RJ, Tannir NM, McDermott DF, et al. nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. doi: 10.1056/NEJMoa1712126. PubMed DOI PMC

Chen YW, Rini BI. approaches to first-line therapy for metastatic clear cell renal cell carcinoma. Curr Oncol Rep. 2022;24(6):695–702. doi: 10.1007/s11912-022-01196-1. PubMed DOI

Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicentre study. J Clin Oncol. 2009;27(34):5794–5799. doi: 10.1200/JCO.2008.21.4809. PubMed DOI

Velaer K, Thomas IC, Yang J, et al. Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: a laboratory wide association study (LWAS) Urol Oncol. 2022;40(1):12.e23–12.e30. doi: 10.1016/j.urolonc.2021.08.011. PubMed DOI PMC

Rebuzzi SE, Perrone F, Bersanelli M, Bregni G, Milella M, Buti S. Prognostic and predictive molecular biomarkers in metastatic renal cell carcinoma patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Mol Diagn. 2020;20(2):169–185. doi: 10.1080/14737159.2019.1680286. PubMed DOI

Fotia G, Stellato M, Guadalupi V, et al. Current Status of Predictive Biomarker Development in Metastatic Renal Cell Carcinoma. Curr Oncol Rep. 2023;25(6):671–677. doi: 10.1007/s11912-023-01395-4. PubMed DOI

Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1α in renal cell carcinoma tumorigenesis. J Mol Med (Berl) 2014;92(8):825–836. doi: 10.1007/s00109-014-1180-z. PubMed DOI PMC

Chakraborty AA. Coalescing lessons from oxygen sensing, tumor metabolism, and epigenetics to target VHL loss in kidney cancer. Semin Cancer Biol. 2020;67(Pt 2):34–42. doi: 10.1016/j.semcancer.2020.03.012. PubMed DOI

Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–296. doi: 10.1200/JCO.2002.20.1.289. PubMed DOI

Tommasi C, Scartabellati G, Giannarelli D, et al. The role of mean corpuscular volume and red cell distribution width in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: the MARECAP retrospective study. Ther Adv Urol. 2023;15:17562872231187216. doi: 10.1177/17562872231187216. PubMed DOI PMC

Yang YH, Ansel S, Meerveld-Eggink A, et al. Baseline and dynamic changes in hemoglobin levels predict treatment response and prognosis in metastatic renal cell carcinoma: a multicentre retrospective study. Clin Genitourin Cancer. 2023;21(4):e242–e251. doi: 10.1016/j.clgc.2023.02.001. PubMed DOI

Johnson AC, Matias M, Boyle H, et al. Hemoglobin level increase as an efficacy biomarker during axitinib treatment for metastatic renal cell carcinoma: a retrospective study. BMC Cancer. 2017;17(1):355. doi: 10.1186/s12885-017-3312-7. PubMed DOI PMC

Tripathi A, Jacobus S, Feldman H, Choueiri TK, Harshman LC. Prognostic significance of increases in hemoglobin in renal cell carcinoma patients during treatment With VEGF-directed therapy. Clin Genitourin Cancer. 2017;15(3):396–402. doi: 10.1016/j.clgc.2016.12.009. PubMed DOI

Rini BI, Choueiri TK, Elson P, et al. Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma. Cancer. 2008;113(6):1309–1314. doi: 10.1002/cncr.23711. PubMed DOI

Bourlon MT, Gao D, Trigero S, et al. Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma. Cancer Med. 2016;5(12):3386–3393. doi: 10.1002/cam4.919. PubMed DOI PMC

Rihacek M, Selingerova I, Kocak I, et al. Sunitinib-induced elevation of mean corpuscular volume (MCV)-exploring its possible clinical relevance in cancer patients. Curr Oncol. 2022;29(6):4138–4147. doi: 10.3390/curroncol29060330. PubMed DOI PMC

Kloth JSL, Hamberg P, Mendelaar PAJ, et al. Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment. Eur J Cancer. 2016;56:101–106. doi: 10.1016/j.ejca.2015.12.019. PubMed DOI

Kucharz J, Giza A, Dumnicka P, et al. Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma. Med Oncol. 2016;33(10):109. doi: 10.1007/s12032-016-0818-9. PubMed DOI PMC

Mazzaschi G, Lazzarin A, Santoni M, et al. Integrating red blood cell features and hemoglobin levels in metastatic renal cell carcinoma patients treated with pazopanib or cabozantinib: an easily exploitable prognostic score. Front Biosci. 2023;15(3):20. doi: 10.31083/j.fbe1503020. PubMed DOI

Lai Y, Zhao Z, Zeng T, et al. Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma. Cancer Cell Int. 2018;18:31. doi: 10.1186/s12935-018-0530-2. PubMed DOI PMC

D’Aniello C, Berretta M, Cavaliere C, et al. Biomarkers of prognosis and efficacy of anti-angiogenic therapy in metastatic clear cell renal cancer. Front Oncol. 2019;9:11. doi: 10.3389/fonc.2019.01400. PubMed DOI PMC

Czarnecka AM, Sobczuk P, Korniluk J, et al. Long-term response to sunitinib: everolimus treatment in metastatic clear cell renal cell carcinoma. Future Oncol. 2017;13(1):31–49. doi: 10.2217/fon-2016-0355. PubMed DOI

Kim SH, Suh YS, Lee DE, et al. A retrospective comparative study of progression-free survival and overall survival between metachronous and synchronous metastatic renal cell carcinoma in intermediate- or poor-risk patients treated with VEGF-targeted therapy. Oncotarget. 2017;8(55):93633–93643. doi: 10.18632/oncotarget.20674. PubMed DOI PMC

Iacovelli R, Farcomeni A, Sternberg CN, et al. Prognostic factors in patients receiving third line targeted therapy for metastatic renal cell carcinoma. J Urol. 2015;193(6):1905–1910. doi: 10.1016/j.juro.2014.11.092. PubMed DOI

Puente J, Laínez N, Dueñas M, et al. Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma. Oncotarget. 2017;8(18):30410–30421. doi: 10.18632/oncotarget.16494. PubMed DOI PMC

Bilir C, Yıldız İ, Bilici A, et al. Is Change in hemoglobin level a predictive biomarker of tyrosine kinase efficacy in metastatic renal cell carcinoma? A Turkish oncology group study. Cancer Invest. 2017;35(4):248–255. doi: 10.1080/07357907.2017.1292518. PubMed DOI

Korkmaz M, Eryılmaz MK, Koçak MZ, et al. Does red blood cell distribution width predict prognosis in metastatic renal cell carcinoma patients using first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy? J Cancer Res Ther. 2023;19(Supplement):S0. doi: 10.4103/jcrt.jcrt_898_22. PubMed DOI

Aktepe OH, Guven DC, Sahin TK, et al. The predictive value of red blood cell distribution width for survival outcomes of metastatic renal cell carcinoma patients treated with targeted therapy. Nutr Cancer. 2021;73(10):1957–1963. doi: 10.1080/01635581.2021.1871925. PubMed DOI