BACKGROUND: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. OBJECTIVE: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. METHODS: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. RESULTS: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. CONCLUSIONS: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

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 Pilsen Czech Republic

Clinical Oncology Sociedad de Oncología y Hematología del Cesar Valledupar Colombia

Department of Experimental Medicine Sapienza University of Rome Rome Italy

Department of Health Sciences Section of Clinical Pharmacology and Oncology University of Florence Florence Italy

Department of Hematology Oncology and Dermatology UOC Oncologia A Policlinico Umberto 1 University Hospital Sapienza University of Rome Rome Italy

Department of Internal Medicine Division of Medical Oncology University of Kansas Cancer Center Westwood KS USA

Department of Medical and Surgical Science University of Bologna Bologna Italy

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

Department of Medical Oncology Cliniques Universitaires Saint Luc Brussels Belgium

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

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

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

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

Department of Radiological Oncological and Pathological Sciences Policlinico Umberto 1 University of Rome Rome Italy

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

Division of Hematology Oncology Department of Medicine Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea

Faculty of Medicine Masaryk University Brno Czech Republic

General Director AST3 Macerata Italy

Hematology Oncology Department Faculty of Medicine Saint Joseph University of Beirut Beirut Lebanon

Hospital Israelita Albert Einstein São Paulo SP Brazil

Hospital Sírio Libanês Brasília DF Brazil

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City Mexico

Interdisciplinary Department of Medicine Division of Medical Oncology University of Bari Aldo Moro AOU Consorziale Policlinico di Bari Bari Italy

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Markey Cancer Center University of Kentucky Lexington KY USA

Masaryk Memorial Cancer Institute Brno Czech Republic

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

Medical Oncology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Medical Oncology IRCCS National Cancer Institute Regina Elena Rome Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

National Cancer Centre Singapore Singapore Singapore

Oncology Unit Macerata Hospital Macerata Italy

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