Effectiveness and safety of first-line therapies, dual immunotherapy versus immunotherapy plus targeted therapy in advanced renal cell carcinoma: A systematic review and meta-analysis

Introduction The preferred first-line regimen in advanced renal cell carcinoma (aRCC) remains uncertain, because rapid evolution of immunotherapy-based combination regimens quickly outdates the existing evidence. Current strategies for synthesizing these data lack clarity and applicability. Thus, we performed a meta-analysis comparing the effectiveness and safety of dual immunotherapy and immunotherapy plus tyrosine kinase inhibitors in aRCC. Methods A systematic search was conducted across two databases, PubMed and the Cochrane Library, for literature published between January 2000 and March 2025. Cohort studies providing direct comparisons of these therapies were included. A random-effect model was utilized to pool hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS). Results Six studies, including 5486 patients, were analyzed. There was no statistically significant difference in progression-free survival between the two interventions (HR 0.92, 95% CI 0.84–1.00, p = 0.06, I 2 = 7%). The OS benefit was similar for both regimens (HR 1.00, 95% CI 0.89–1.12, p = 1.00, I 2 = 0%). Limited availability of safety data precluded a comprehensive assessment of their toxicity profiles. Conclusion The findings of this meta-analysis do not support a definitive preference for either of the immunotherapy combinations. Nevertheless, given the low certainty of retrospective data, randomized controlled trials and prospective cohort studies are needed to inform evidence-based clinical decisions.