First-line immune checkpoint inhibitor plus anti-angiogenic therapy for advanced renal cell carcinoma: a meta-analysis of randomized controlled trials
Background The meta-analysis assesses the efficacy and safety of first-line immune checkpoint inhibitors (ICIs) plus anti-angiogenic therapies versus sunitinib in advanced or metastatic renal cell carcinoma (RCC). The analysis places focus on differential benefits across International Metastatic RCC Database Consortium (IMDC) risk subgroups, ICI classes, and anti-angiogenic drug classes. Methods We systematically searched the Cochrane Library, Embase and PubMed for randomized controlled trials (RCTs) comparing ICI plus anti-angiogenic therapy with sunitinib as first-line treatment for advanced RCC. Efficacy measures included progression-free survival (PFS) and overall survival (OS), objective response rate (ORR), disease control rate (DCR). Safety measures assessed grade ≥3 treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation. Results Seven RCTs involving 4,977 patients were included. Combination therapy was associated with significant improvements in PFS (0.63, [0.54–0.72]), OS (0.83, [0.77–0.89]), ORR (3.07, [2.01–4.67]), and DCR (2.04, [1.49–2.78]) (all P < 0.001). OS benefits were most marked in poor-risk (HR = 0.52) and intermediate-risk (HR = 0.88) patients, while favorable-risk patients showed no significant OS gain (0.97, [0.79–1.18]). Multi-targeted tyrosine kinase inhibitor (TKI)-based regimens provided the greatest PFS and ORR benefits but the highest toxicity, while vascular endothelial growth factor receptor (VEGFR)-selective TKIs showed a balanced efficacy-safety profile. Anti-VEGF monoclonal antibody-based combinations failed to demonstrate significant OS or ORR advantages over sunitinib. Safety analysis showed no significant difference in grade ≥3 TRAEs (1.22, [0.94–1.58]), but did reveal a significantly increased risk of treatment discontinuation (3.34, [2.77–4.03]). Additionally, elevated risks of hepatotoxicity, hypertension, and proteinuria were observed, whereas hematologic toxicities and fatigue were significantly reduced versus sunitinib. Conclusion TKI-based ICI combination therapy is superior to sunitinib as first-line treatment for advanced RCC, particularly in intermediate- and poor-risk patients. Anti-angiogenic agent class is the primary determinant of efficacy and tolerability, while ICI class does not influence regimen selection. These findings support a risk-adapted, class-informed approach to optimize therapeutic outcomes in clinical practice. Systematic Review registration Identifier CRD420251273931.