Background 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. Methods 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. Results 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. Conclusion 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.
Beas-Lozano et al. (Mon,) studied this question.