Immune-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC) and have positively impacted survival outcomes in phase III clinical trials. However, these trials are conducted in highly selected populations and controlled settings, which may limit the generalizability of toxicity profiles to routine clinical practice. Real-world data are therefore essential to better characterize the incidence and determinants of severe adverse events (AEs) associated with immune-based combinations.
We conducted a multinational, retrospective analysis of the ARON-1 registry, of patients with mRCC who received first-line immune-based combination therapy across 17 countries. The primary endpoint was to evaluate the real-world incidence of grade 3-4 (G3-G4) AEs. Logistic regression analyses were performed to identify clinical factors associated with toxicity. Overall survival (OS) was assessed using Kaplan-Meier methods, with landmark analyses to explore the association between G3-G4 AEs and survival outcomes.
Among 2, 401 patients receiving immune-based combinations, 1, 921 (80%) had complete data on grade 3-4 AEs and were included in the analysis. G3-G4 AEs occurred in 34% (n=653). Pembrolizumab plus lenvatinib was associated with the highest incidence of high-grade AEs, whereas nivolumab plus ipilimumab showed the lowest. Older age and female sex were independently associated with an increased risk of G3-G4 toxicity. Although the occurrence of severe AEs was associated with improved OS in unadjusted analyses, this association was non-significant in the 6-month landmark analyses.
In this large, multinational real-world cohort, the incidence of G3-G4 adverse events in patients with mRCC treated with immune-based combinations was lower than that reported in pivotal clinical trials, underscoring meaningful differences between trial and routine practice settings. Patient- and regimen-specific factors significantly influenced toxicity risk. These findings highlight the complementary role of real-world evidence in informing toxicity management and support individualized treatment strategies to optimize outcomes in everyday clinical practice.
Frontiers in immunology. 2026 Apr 20*** epublish ***
Evelyn L Beas-Lozano, Sarah Scagliarini, Paola I Valdez-Sandoval, María Fernanda Esparza-Orozco, Mehmet Asin Bilen, Aristotelis Bamias, Haoran Li, Maria José Juan Fita, Jindrich Kopecky, Ray Manneh Kopp, Marwan Ghosn, Andre Poisl Fay, Dipen Bhuva, Jakub Kucharz, Thomas Büttner, Javier Molina-Cerrillo, Ondrej Fiala, Alessandro Rizzo, Brigida Anna Maiorano, Andrey Soares, Sebastiano Buti, Fernando Sabino Marques Monteiro, Francesco Massari, Matteo Santoni, Maria T Bourlon
Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Department of Medical Oncology, AORN "A. Cardarelli", Naples, Italy., Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, United States., 2nd Propaedeutic Department of Internal Medicine, ATTIKON University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Kansas City, MO, United States., Fundación Instituto Valenciano de Oncología, Profesor Beltrán Baguena, Valencia, Spain., Department of Clinical Oncology and Radiotherapy, University Hospital Hradec Kralove, Hradec Kralove, Czechia., Department of Clinical Oncology, Clinical Oncology, Sociedad de Oncología y Hematología del Cesar, Valledupar, Colombia., Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon., Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) School of Medicine, Porto Alegre, RS, Brazil., Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India., Department of Uro-Oncology, Maria Sklodowska-Curie National Research Institute of Oncology Warsaw, Warsaw, Poland., Department of Urology, University Hospital Bonn (UKB), Bonn, Germany., Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain., Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czechia., S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II", Bari, Italy., Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Hospital, Milan, Italy., Oncology Unit, Eistein Hospital Israelita, São Paulo, SP, Brazil., Medical Oncology Unit, University Hospital of Parma, Parma, Italy., Latin American Cooperative Oncology Group - LACOG, Porto Alegre, Brazil., Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Medical Oncology Unit, Macerata Hospital, Macerata, Italy.