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.
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.
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 vs. 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% vs 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.
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.
Annals of oncology : official journal of the European Society for Medical Oncology. 2025 Apr 01 [Epub ahead of print]
L Bergmann, L Albiges, M Ahrens, M Gross-Goupil, E Boleti, G Gravis, A Fléchon, M-O Grimm, J Bedke, P Barthélémy, D Castellano, B Mellado, P Ivanyi, S Rottey, A Flörcken, C Suarez, P Maroto, V Grünwald, S F Oosting, J Kopecky, S Zschäbitz, M Boegemann, T Buchler, G Niegisch, P J Goebell, T Waddell, F Joly, F Priou, M Retz, S Siemer, U Zimmermann, D Deckbar, I Burkholder, A Hartmann, J B Haanen, Interdisciplinary Renal Cell Carcinoma Working Group of the DKG (IAGN)
Medical Clinic II, University Hospital Frankfurt, Frankfurt, Germany. Electronic address: ., Institut Gustave Roussy, Paris, Paris, France., Medical Clinic II, University Hospital Frankfurt, Frankfurt, Germany., Medical Oncology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France., Royal Free London NHS Foundation Trust, London, UK., Institut Paoli-Calmettes, Department of Medical Oncology, Aix Marseille Univ, INSERM, CNRS, CRCM, Immunity and Cancer Team, Marseille, France., Centre Léon Bérard, Lyon, France., Jena University Hospital, Department of Urology and Comprehensive Cancer Center Central Germany, Jena, Germany., Dept. of Urology, Eberhard Karls University Tübingen, Tübingen, Germany; now Dept. of Urology & Transplantation Surgery, Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany., Medical Oncology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France., Hospital Universitario, Madrid, Spain., Hospital Clinic de Barcelona, Barcelona, Spain., Medical School, Department of Hematology and Oncology, Hanover, Germany., Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium., Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology, Berlin, Germany., Hospital Universitari Vall d´Hebron, Vall d´Hebron Barcelona Hospital Campus, Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain., Sant Pau Hospital (Hospital de la Santa Creu i Sant Pau), Barcelona, Spain., Clinic for Urology and Clinic for Medical Oncology, University Hospital, , Essen, Germany., University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands., Faculty Hospital Hradec Kralove, Hradec Kralove, Czech Republic., University Hospital, NCT Heidelberg, Heidelberg, Germany., University Hospital Münster, Clinic for Urology, Münster, Germany., Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital , Prague, Czech Republic., Department of Urology, Medical Faculty and University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Erlangen University Hospital, Department of Urology and Pediatric Urology, Erlangen, Germany., The Christie NHS Foundation Trust, Manchester, UK., Centre Régional de Lutte contre le Cancer François Baclesse, Caen, France., Hospital Center Departmental De Vendée, La-Roche-sur-Yon, France., Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany., Department of Urology, Saarland University, Homburg/Saar, Germany., University Medical Center Greifswald, Clinic for Urology, Greifswald, Germany., Department of Health Sciences, University of Applied Sciences, Fulda, Germany., Institute of Pathology University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) , Erlangen, Germany; Comprehensive Cancer Center Erlangen EMN (CCC ER-ERM), Erlangen, Germany., Netherlands Cancer Institute, Amsterdam, the Netherlands.