INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria. MATERIALS AND METHODS: This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months). CONCLUSIONS: The choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

Alcalá University Madrid Spain

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 Internal Medicine and Medical Specialties University of Genoa Genoa Italy

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

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

Department of Medical Oncology AUSL Della Romagna Ospedale Civile Degli Infermi Faenza Italy

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

Department of Medical Oncology Maggiore Della Carità University Hospital 28100 Novara Italy

Department of Medical Oncology San Camillo Forlanini Hospital Rome Italy

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

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

Department of Surgical Oncological and Oral Sciences Section of Medical Oncology University of Palermo Palermo Italy

Division of Medical Oncology National Cancer Centre Singapore Singapore Singapore

Division of Oncology Institute for Cancer Research and Treatment Asl Cn2 Alba Brà 12051 Alba Brà Italy

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

Hospital Israelita Albert Einstein São Paulo SP Brazil

Interdisciplinary Department of Medicine University of Bari Aldo Moro and Division of Medical Oncology A O U Consorziale Policlinico Di Bari Piazza Giulio Cesare 11 70124 Bari Italy

IRCCS Ospedale Policlinico San Martino Genoa Italy

Klinik Für Urologie Ratzeburger Allee 160 23538 Lübeck Germany

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

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

Medical Oncology Ospedale Santa Corona 17027 Pietra Ligure Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

Medical Oncology Unit University Hospital of Parma Department of Medicine and Surgery University of Parma Parma Italy

Oncology and Hematology Department Hospital Sirio Libanês SGAS 613 Lote 94 Brasília DF Brazil

Oncology Unit A R N A S Civico Palermo Italy

Oncology Unit Macerata Hospital Macerata Italy

Ospedale San Paolo Medical Oncology 17100 Savona Italy

Section of Innovation Biomedicine Oncology Area Department of Engineering for Innovation Medicine University of Verona Verona Italy

SOC Oncologia PO Pugliese Ciaccio Azienda Ospedaliera Universitaria Renato Dulbecco Catanzaro Italy

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