BACKGROUND: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. OBJECTIVE: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. METHODS: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). CONCLUSIONS: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

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

Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 76 Pilsen Czech Republic

Clinical Oncology Sociedad de Oncología y Hematología del Cesar Valledupar Colombia

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

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 Universidad Francisco de Vitoria Madrid Spain

Department of Medical Oncology Università Politecnica delle Marche AOU delle Marche Ancona Italy

Department of Medical Surgical Sciences and Biotechnologies Sapienza University Policlinico Umberto1 Rome Italy

Department of Medicine and Surgery Federico 2 University Naples Italy

Department of Medicine and Surgery University of Parma Via Gramsci 14 43126 Parma Italy

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

Department of Oncology and Radiotherapeutics Faculty of Medicine University Hospital in Pilsen Charles University Prague Alej Svobody 80 304 60 Pilsen Czech Republic

Department of Uro oncology Maria Sklodowska Curie National Research Institute of Oncology 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 Oncology Department of Oncology and Hematology University Hospital of Modena 41124 Modena Italy

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

Latin American Cooperative Oncology Group LACOG and Oncology and Hematology Department Hospital Sirio Libanês SGAS 613 Lote 94 Brasília DF Brazil

Markey Cancer Center University of Kentucky Lexington KY 40536 0293 USA

Medical Oncology 1 IRCCS Regina Elena National Cancer Institute Rome Italy

Medical Oncology Cliniques universitaires Saint Luc Centre Hospitalier de Jolimont Institut Roi Albert 2 Haine Saint Paul Brussels Belgium

Medical Oncology Department La Paz University Hospital Madrid Spain

Medical Oncology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

National Cancer Centre Singapore Singapore

Oncology 1 Unit Department of Oncology Istituto Oncologico Veneto IOV IRCCS Padova Italy

Oncology Operative Unit Santa Maria delle Grazie Hospital ASL NA2 NORD Pozzuoli Naples 80078 Italy

Oncology Unit A R N A S Civico Palermo Italy

Oncology Unit Macerata Hospital Macerata Italy

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

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