First-line Therapy for Metastatic Renal Cell Carcinoma: An Updated Network Meta-analysis using Final Follow-up Data

CONTEXT AND OBJECTIVE: Although immune checkpoint inhibitor (ICI)-based combination therapies are recommended for metastatic renal cell carcinoma (mRCC), no comprehensive network meta-analysis (NMA) has synthesized the final follow-up data available from randomized controlled trials (RCTs). Thus, we aimed to compare the first-line ICI-based combination therapies in patients with mRCC using final follow-up data from pivotal phase 3 RCTs. EVIDENCE ACQUISITION: Three databases were searched in June 2025 to identify RCTs evaluating oncologic outcomes in patients with mRCC who were treated with first-line ICI-based combination therapies. We conducted frequentist NMA to compare the oncological and safety outcomes. Subgroup analyses were also performed by International mRCC Database Consortium (IMDC) risk classification and metastatic site. EVIDENCE SYNTHESIS: Five RCTs comprising 4206 patients were included in the NMAs. In the overall population, treatment ranking indicated that nivolumab/ipilimumab (87%) had the highest probability of improved overall survival (OS), while pembrolizumab/lenvatinib ranked the highest for progression-free survival (PFS; 99%) and objective response rates (ORRs; 96%), as well as for complete response (CR) rates (87%). These findings were consistent in patients with intermediate-/poor-risk disease, although nivolumab/ipilimumab had the highest likelihood of achieving a CR rate of 81%. In patients with bone metastasis, nivolumab/cabozantinib ranked the highest for OS, PFS, and ORR. The validity of this NMA may be found limited, in that it relies on the quality and reliability of the studies included, potentially leading to bias. Again, as the rigorous interpretation of surface under the cumulative ranking curve analyses proved difficult in this NMA, caution should be exercised in their interpretation. CONCLUSIONS: Nivolumab/ipilimumab remains a compelling treatment option for patients with intermediate-/poor-risk disease. Among ICI + tyrosine kinase inhibitor combinations, nivolumab/cabozantinib and pembrolizumab/lenvatinib offered comparable OS benefits, while pembrolizumab/lenvatinib appeared as a more favorable option in delaying disease progression. Differential treatment rankings based on IMDC risk classification and metastatic sites may enhance clinical decision-making.