BACKGROUND: The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting. METHODS: Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazard models, and chi-square tests. RESULTS: A total of 760 patients with a median age of 64 years (range, 29-88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively (P = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS. CONCLUSIONS: In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

2nd Propaedeutic Department of Internal Medicine School of Medicine ATTIKON University Hospital National and Kapodistrian University of Athens Athens Greece

Clinical Oncology Sociedad de Oncología y Hematología del Cesar Valledupar Colombia

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czechia

Department of Genitourinary Medical Oncology and Clinical Pharmacology National Institute of Oncology Budapest Hungary

Department of Health Sciences Section of Clinical Pharmacology and Oncology University of Florence Viale Pieraccini 6 50139 Florence Italy

Department of Medical Oncology Army Hospital Research and Referral New Delhi India

Department of Medical Oncology Cliniques Universitaires Saint Luc 1200 Brussels Belgium

Department of Medical Oncology IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Meldola Italy

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

Department of Medical Oncology San Camillo Forlanini Hospital Rome Italy

Department of Obstetrics Radiotherapy Alexandru Trestioreanu Institute of Oncology Carol Davila University of Medicine and Pharmacy Prof Dr Bucharest Romania

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Prague Czech Republic

Department of Oncology and Hematology University Hospital of Modena Modena Italy

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

Department of Uro Oncology Maria Sklodowska Curie National Research Institute of Oncology Warsaw Warsaw Poland

Department of Urology Medical University of Innsbruck Anichstrasse 35 6020 Innsbruck Austria

Department of Urology University Hospital Bonn 53127 Bonn Germany

Division of Medical Oncology National Cancer Centre Singapore Singapore Singapore

Division of Oncology Department of Internal Medicine Medical University of Graz Augenbruggerplatz 15 8010 Graz Austria

Finnish Medicines Agency Fimea Tampere Finland

Hematology and Oncology Department Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City Mexico

Hospital Ramón y Cajal Madrid Spain

Interdisciplinary Department of Medicina University of Bari Aldo Moro and Division of Medical Oncology A O U Consorziale Policlinico Di Bari Bari Italy

Markey Cancer Center University of Kentucky Lexington KY 40536 0293 USA

Medical Oncology Department CHU Insular Materno Infantil Las Palmas de Gran Canaria Spain

Medical Oncology Department La Paz University Hospital Madrid Spain

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Via Albertoni 15 Bologna Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

Medical Oncology Unit Santa Chiara Hospital Trento Italy

Medical Oncology Unit University Hospital of Parma 43126 Parma Italy

Oncology 3 Unit Department of Oncology Istituto Oncologico Veneto IOV IRCCS Padua Italy

Oncology Unit Macerata Hospital Macerata Italy

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

Urologic Oncology Champalimaud Clinical Center 1400 038 Lisbon Portugal

Zobrazit více v PubMed

Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. 10.3322/CAAC.21660 PubMed

Cheville JC, Lohse CM, Zincke H et al (2003) Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 27:612–624. 10.1097/00000478-200305000-00005 PubMed

Dabestani S, Thorstenson A, Lindblad P et al (2016) Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 34:1081–1086. 10.1007/s00345-016-1773-y PubMed

Motzer RJ, Bacik J, Murphy BA et al (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289–296. 10.1200/jco.2002.20.1.289 PubMed

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

Rini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116–1127. 10.1056/nejmoa1816714 PubMed

Choueiri TK, Powles T, Burotto M et al (2021) Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829–841. 10.1056/nejmoa2026982 PubMed PMC

Motzer R, Alekseev B, Rha S-Y et al (2021) Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 384:1289–1300. 10.1056/nejmoa2035716 PubMed

Motzer RJ, Penkov K, Haanen J et al (2019) Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103–1115. 10.1056/nejmoa1816047 PubMed PMC

Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277–1290. 10.1056/nejmoa1712126 PubMed PMC

Shah NJ, Sura SD, Shinde R et al (2023) Real-world treatment patterns and clinical outcomes for metastatic renal cell carcinoma in the current treatment era. Eur Urol Open Sci 49:110. 10.1016/J.EUROS.2022.12.015 PubMed PMC

Santoni M, Massari F, Myint ZW et al (2023) Global real-world outcomes of patients receiving immuno-oncology combinations for advanced renal cell carcinoma: the ARON-1 study. Target Oncol 18:559–570. 10.1007/s11523-023-00978-2 PubMed

Santoni M, Massari F, Myint ZW et al (2023) Clinico-pathological features influencing the prognostic role of body mass index in patients with advanced renal cell carcinoma treated by immuno-oncology combinations (ARON-1). Clin Genitourin Cancer. 10.1016/j.clgc.2023.03.006 PubMed

Santoni M, Buti S, Myint ZW et al (2023) Real-world outcome of patients with advanced renal cell carcinoma and intermediate- or poor-risk international metastatic renal cell carcinoma database consortium criteria treated by immune-oncology combinations: differential effectiveness by risk group? Eur Urol Oncol. 10.1016/j.euo.2023.07.003 PubMed

Porta C, Bamias A, Zakopoulou R et al (2023) Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations. Minerva Urol Nephrol 75:460–470 PubMed

Schwartz LH, Litière S, De Vries E et al (2016) RECIST 1.1—update and clarification: from the RECIST committee. Eur J Cancer 62:132–137. 10.1016/j.ejca.2016.03.081 PubMed PMC

(2019) FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. Case Med Res. 10.31525/fda1-ucm636395.htm

Rini BI, Plimack ER, Stus V et al (2023) Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol 41(17_suppl):LBA4501–LBA4501. 10.1200/JCO.2023.41.17_suppl.LBA4501

FDA Approves Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma—The ASCO Post. https://ascopost.com/issues/february-10-2021/fda-approves-nivolumab-plus-cabozantinib-for-advanced-renal-cell-carcinoma/. Accessed 27 Oct 2023

Choueiri TK, Powles T, Burotto M et al (2020) 696O_PR Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol 31:S1159. 10.1016/j.annonc.2020.08.2257

Burotto M, Powles T, Escudier B et al (2023) Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol 41:603–603. 10.1200/JCO.2023.41.6_suppl.603

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 4:755–765. 10.1016/j.euo.2021.03.001 PubMed

Bin RI, He H, Ryu AJ et al (2021) A living, interactive systematic review and network meta-analysis of first-line treatment of metastatic renal cell carcinoma [formula presented]. Eur Urol 80:712–723 PubMed

Lombardi P, Filetti M, Falcone R et al (2022) New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Cancer Treat Rev 106:102377. 10.1016/j.ctrv.2022.102377 PubMed

Catalano M, Procopio G, Sepe P et al (2023) Tyrosine kinase and immune checkpoints inhibitors in favorable risk metastatic renal cell carcinoma: Trick or treat? Pharmacol Ther. 10.1016/J.PHARMTHERA.2023.108499 PubMed

Yanagisawa T, Kawada T, Quhal F et al (2023) Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis. World J Urol 41:1763–1774. 10.1007/s00345-023-04412-0 PubMed PMC

Satkunasivam R, Guzman JC, Klaassen Z et al (2022) Association between prior nephrectomy and efficacy of immune checkpoint inhibitor therapy in metastatic renal cell carcinoma—a systematic review and meta-analysis. Urol Oncol Semin Orig Investig 40:64.e17-64.e24. 10.1016/j.urolonc.2021.09.009 PubMed PMC

Yanagisawa T, Quhal F, Kawada T et al (2023) Association between age and efficacy of first-line immunotherapy-based combination therapies for mRCC: a meta-analysis. Immunotherapy. 10.2217/IMT-2023-0039 PubMed