Nivolumab improved survival in patients with refractory metastatic clear-cell renal cell carcinoma (ccRCC), but no reliable biomarker of activity has been identified. We conducted a real-world phase 2 trial of nivolumab in patients progressing after one or more vascular endothelial growth factor (VEGF) receptor-directed therapies, which included an integrated translational programme.
Candidate tissue and circulating biomarkers were assessed using immunoassays and gene expression profiling. Overall, 720 patients were treated, with activity and safety in line with pivotal trial data. Exploration of tissue architecture showed that the presence of tertiary lymphoid structures, CD8+ lymphocytes, and CD163+ macrophage infiltration at the invasive margin were all marginally associated with longer progression-free survival, similarly to PD-1 expression on immune cells. Expression of hypoxia-related marker VEGF on tumour cells was however strongly associated with shorter progression-free and overall survival. Recapitulation of microenvironment composition based on gene expression signatures showed that patients harbouring a high tumour lymphocyte infiltration, concomitantly to low infiltration of neutrophil and non-immune stromal cells, had improved response to nivolumab. Conversely, circulating cytokines related to protumoral inflammation interleukin (IL)-6 and IL-8 were independently associated with shorter progression-free and overall survival. Overall, immune and angiogenic features helped inform outcomes to nivolumab. Circulating factors were best potential predictors for immunotherapy activity in ccRCC.
European urology. 2025 Nov 11 [Epub ahead of print]
Ronan Flippot, Yann-Alexandre Vano, Cécile Dalban, Benoit Beuselinck, Aude Fléchon, Maxime Meylan, Damien Pouessel, Antoine Bougoüin, Catherine Sautes-Fridman, Gwenaelle Gravis, Nathalie Chaput, Stéphane Oudard, Aude Desnoyer, Brigitte Laguerre, Salem Chouaib, Philippe Barthelemy, Delphine Borchiellini, Lucia Carril-Ajuria, Marine Gross-Goupil, Wolf-Herman Fridman, Lionnel Geoffrois, Frederic Rolland, Antoine Thiery-Vuillemin, Florence Joly, Sylvain Ladoire, Florence Tantot, Sylvie Chabaud, Bernard Escudier, Nathalie Rioux-Leclercq, Laurence Albiges, NIVOREN GETUG-AFU 26 investigators
Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France., Centre de Recherche des Cordeliers, INSERM UMR S1138, Université́ Paris Cité, Sorbonne Université, Paris, France; Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP Centre - Université́ Paris Cité, Paris, France., Direction de la Recherche Clinique et de l'Innovation, Pôle statistique, Centre Léon Bérard, Lyon, France., Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium., Department of Medical Oncology, Centre Léon Bérard, Lyon, France., Centre de Recherche des Cordeliers, INSERM UMR S1138, Université́ Paris Cité, Sorbonne Université, Paris, France., Institut Claudius Regaud - Comprehensive Cancer Center, IUCT, Oncopole, Toulouse, France., Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France., Immunomonitoring in Oncology Laboratory, CNRS UMS 3655 and INSERM US 23, Paris Saclay University, Villejuif, France., Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP Centre - Université́ Paris Cité, Paris, France; INSERM U970, PARCC, Université Paris-Cité, Paris, France., Centre Eugène Marquis, Rennes, France., INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, Villejuif, France., Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France., Department of Medical Oncology, Centre Antoine Lacassagne, Université Côte d'Azur, Nice, France., Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France; Medical Oncology, CHU Brugmann, Bruxelles, Belgium., Department of Medical Oncology, Saint-André University Hospital, Bordeaux, France., Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France., Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Centre René Gauducheau, Nantes, France., Centre hospitalo-universitaire de Besançon, Université de Bourgogne, Besançon, France; EFS-BFC, UMR 1098, Besançon, France; Département d'oncologie médicale, Inserm, Besançon, France., Medical Oncology Department, Centre François Baclesse, Caen, France., Department of Medical Oncology, Georges-François Leclerc Cancer Center, Dijon, France., GETUG Group, UNICANCER, France., Service d'anatomie et cytologie pathologiques, CHU de Rennes, Rennes, France., Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41224576