BACKGROUND: Non-clear cell renal cell cancers (nccRCCs) are a heterogeneous group of more than 20 different entities, but are rarely included in large, randomized trials. Tyrosine kinase inhibitors with or without immune checkpoint inhibition are considered as a standard of care (SOC), but optimal treatment is not yet defined. We designed the first prospective randomized trial comparing ipilimumab/nivolumab to SOC. PATIENTS AND METHODS: We randomized adult patients with previously untreated advanced or metastatic nccRCC 1:1 to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by fixed dose nivolumab of 240 mg every 2 weeks or 480 mg every 4 weeks or to SOC. Patients were stratified by histology and by IMDC risk score. Central pathology review was mandatory. The primary endpoint was the overall survival (OS) rate at 12 months, secondary endpoints included median OS, response rate, progression-free survival (PFS), safety and quality of life. RESULTS: In total, 157 patients were assigned to receive ipilimumab/nivolumab, and 152 to SOC. The 12-month survival rate was 78% with ipilimumab/nivolumab [95% confidence interval (CI) 71-84%] compared to 68% with SOC (95% CI 60-75%, P = 0.026). Median OS was 33.2 months versus 25.2 months, P = 0.163 [HR 0.81 (0.61-1.099)]. PFS was similar in both arms [HR 0.99 (0.77-1.28)]. The ORR was 32.8% versus 19.3%. No major differences between papillary and non-papillary RCC subtypes were observed for any endpoint. Exploratory analysis showed a significant OS advantage [HR 0.56 (95% CI 0.37-0.86)] associated with a PD-L1 CPS score ≥1. Treatment discontinuation due to toxicity occurred in 27 patients (17%) with ipilimumab/nivolumab and 13 patients (9%) with SOC. CONCLUSIONS: Ipilimumab/nivolumab demonstrated a significantly longer OS at the 12-month milestone and an acceptable toxicity profile. Our results therefore underline a relevant clinical benefit of ipilimumab/nivolumab in previously untreated nccRCC entities compared to current SOC.

Centre Léon Bérard Lyon France

Centre Régional de Lutte contre le Cancer François Baclesse Caen France

Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Department of Hematology Oncology and Tumor Immunology Berlin Germany

Clinic for Urology and Clinic for Medical Oncology University Hospital Essen Germany

Department of Health Sciences University of Applied Sciences Fulda Germany

Department of Medical Oncology Ghent University Hospital Ghent Belgium

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer University Hospital Prague Czech Republic

Department of Urology Eberhard Karls University Tübingen Tübingen Germany; Department of Urology and Transplantation Surgery Eva Mayr Stihl Cancer Center Klinikum Stuttgart Stuttgart Germany

Department of Urology Medical Faculty and University Hospital Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Urology Saarland University Homburg Saar Germany

Erlangen University Hospital Department of Urology and Pediatric Urology Erlangen Germany

Faculty Hospital Hradec Kralove Hradec Kralove Czech Republic

Hospital Center Departmental De Vendée La Roche sur Yon France

Hospital Clinic de Barcelona Barcelona Spain

Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Medical Oncology Vall d'Hebron Institute of Oncology Barcelona Spain

Hospital Universitario Madrid Spain

Institut Gustave Roussy Paris France

Institut Paoli Calmettes Department of Medical Oncology Aix Marseille Univ INSERM CNRS CRCM Immunity and Cancer Team Marseille France

Institute of Pathology University Hospital Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Jena University Hospital Department of Urology and Comprehensive Cancer Center Central Germany Jena Germany

Medical Clinic 2 University Hospital Frankfurt Frankfurt Germany

Medical Oncology Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Medical Oncology Institut de Cancérologie Strasbourg Europe Strasbourg France

Medical School Department of Hematology and Oncology Hanover Germany

Netherlands Cancer Institute Amsterdam the Netherlands

Rechts der Isar Medical Center Technical University of Munich Munich Germany

Royal Free London NHS Foundation Trust London UK

Sant Pau Hospital Barcelona Spain

The Christie NHS Foundation Trust Manchester UK

University Hospital Münster Clinic for Urology Münster Germany

University Hospital NCT Heidelberg Heidelberg Germany

University Medical Center Greifswald Clinic for Urology Greifswald Germany

University Medical Centre Groningen University of Groningen Groningen the Netherlands

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