Objective <p>The purpose of this study was to indirectly compare pembrolizumab + lenvatinib to other treatments of interest for first-line advanced renal cell carcinoma (aRCC).</p> Methods <p>A systematic literature review searched EMBASE, MEDLINE, and CENTRAL databases for relevant randomized controlled trials of interest up to 30 January 2024, with an updated search conducted on 17 March 2025. A fixed effect Bayesian network meta-analysis (NMA) was conducted to determine the relative treatment effects for overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).</p> Results <p>When comparing against other immune checkpoint inhibitors (ICI), a statistically significant improvement in PFS was demonstrated between pembrolizumab + lenvatinib compared with nivolumab + ipilimumab (hazard ratio (HR) = 0.53; 95% credible interval (CrI): 0.40–0.71), avelumab + axitinib (HR = 0.71; 95% Crl: 0.53–0.94), atezolizumab + bevacizumab (HR = 0.54; 95% CrI: 0.40–0.73), and pembrolizumab + axitinib (HR = 0.69; 95% CrI: 0.51–0.91). Treatment with pembrolizumab + lenvatinib resulted in no statistically significant difference between pembrolizumab + lenvatinib and other combination ICI-based therapies for OS. A statistically significant higher ORR was shown for pembrolizumab + lenvatinib compared with nivolumab + ipilimumab (odd ratio (OR) = 3.29; 95% Crl: 2.21–4.93), pembrolizumab + axitinib (OR = 1.92; 95% CrI: 1.27–2.94), atezolizumab + bevacizumab (OR = 4.05; 95% Crl: 2.71–6.05), bempegaldesleukin + nivolumab (OR = 6.20; 95% CrI: 3.69–10.48), and nivolumab (OR = 5.92; 95% CrI: 2.70–13.24).</p> Conclusions <p>The overall population analysis indicated that pembrolizumab + lenvatinib improves PFS and ORR compared with other approved ICI combination therapies in first-line aRCC. No significant differences in OS were observed between pembrolizumab + lenvatinib and other combination immune checkpoint inhibitor-based therapies.</p>