To systematically evaluate the efficacy and safety of different combination regimens based on immune checkpoint inhibitors (ICI) as first-line treatment for advanced or metastatic renal cell carcinoma (RCC), and provide evidence for clinical treatment selection.

A comprehensive search of electronic databases was conducted, including PubMed, The Cochrane Library, Embase, Web of Science, CNKI, and Wanfang Data from inception until January 30, 2025, for relevant randomized controlled trial (RCT). After literature screening, data extraction, and risk of bias assessment for the included studies were performed independently by two investigators, a network Meta-analysis was performed using R software version 4.5.0.

A total of seven RCT involving eight treatment interventions were included. Network Meta-analysis results showed that for overall survival (OS), a statistically significant difference was observed only between atezolizumab plus bevacizumab and nivolumab plus ipilimumab, with no significant differences detected among other regimen comparisons. Cumulative ranking probabilities indicated that toripalimab plus axitinib had the highest probability of being the most effective regimen for OS. Regarding progression-free survival (PFS), lenvatinib plus pembrolizumab was identified as the most effective intervention. It demonstrated a statistically significant reduction in the risk of disease progression compared to several other regimens, including atezolizumab plus bevacizumab, avelumab plus axitinib, nivolumab plus ipilimumab, and pembrolizumab plus axitinib. For objective response rate (ORR), nivolumab plus cabozantinib and lenvatinib plus pembrolizumab were associated with higher ORR, with both showing significant superiority to regimens such as pembrolizumab plus axitinib. In terms of safety, the incidence of grade ≥3 treatment-related adverse events (TRAE) was significantly lower with nivolumab plus ipilimumab and atezolizumab plus bevacizumab compared to the other combination regimens. However, no statistically significant difference in TRAE was found between them.

In the first-line treatment of advanced or metastatic RCC, ICI combination regimens generally demonstrated superior efficacy compared to sunitinib. No statistically significant differences in OS were observed for most comparisons between the combination regimens. However, statistically significant differences were detected among specific regimens in terms of PFS, ORR, and TRAE. Their relative rankings need further confirmation through more head-to-head studies in the future.