Combination immunotherapy in Japanese patients with advanced renal cell carcinoma: bridging gaps between clinical trials, real-world evidence, and the potential value of adverse events-a narrative review.

Background and Objective: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced renal cell carcinoma (aRCC), leading to the adoption of combination regimens. Either dual ICI regimens or ICI plus tyrosine kinase inhibitor (TKI) are now established as the first-line standard treatment. While phase III trials have demonstrated significant survival benefits of ICI combination therapy over TKI monotherapy, real-world reports, particularly from Japan, have revealed variable outcomes influenced by patient and tumor characteristics. Treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), are increasingly recognized not only as safety concerns but also as potential predictive biomarkers. In this review, we aimed to compare the clinical trials and real-world outcomes of combination immunotherapy with a focus on Japanese patients, and to examine the prognostic significance of TRAEs. Methods: A narrative literature review was conducted using PubMed and Scopus for English-language studies published between April 2018 and August 2025. Search terms included the following MeSH terms: kidney neoplasm, carcinoma, renal cell, immunotherapy, nivolumab, ipilimumab, pembrolizumab, avelumab, axitinib, cabozantinib, lenvatinib, and biomarkers; and free-text terms: advanced, combination immunotherapy, irAEs, and TRAEs. Phase III trials and retrospective/prospective real-world studies were included, and abstracts and case reports were excluded. Key Content and Findings: Nivolumab plus ipilimumab (NIVO + IPI) and various ICI + TKI regimens (avelumab + axitinib, pembrolizumab + axitinib, nivolumab + cabozantinib, pembrolizumab + lenvatinib) have shown superior efficacy to sunitinib in pivotal trials. Real-world Japanese cohorts often include older patients with poor performance status and non-clear cell RCC (ncc-RCC), leading to shorter overall survival (OS) and progression-free survival (PFS), despite comparable objective response rates (ORRs) to trials. Several studies on patients treated with NIVO + IPI have demonstrated that TRAEs/irAEs are associated with improved ORR and OS, with multivariate analyses identifying them as independent, favorable prognostic factors. However, this correlation was less consistent in ICI + TKI regimens, in which toxicity may be derived from either component. Conclusions: Combination immunotherapy offers substantial benefits for aRCC; however, real-world outcomes can differ from trial data owing to patient heterogeneity. TRAEs show promise as prognostic markers in NIVO + IPI but require further validation in ICI + TKI. Prospective multicenter registries with standardized adverse event reporting, coupled with translational studies, are needed to refine regimen selection and personalized therapy.