Background: The CLEAR trial showed statistically significant improvements in overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and complete response (CR) in subjects treated with lenvatinib plus pembrolizumab (L+P) vs. sunitinib. We conducted an indirect treatment comparison to investigate the comparative efficacy of L+P vs. other first-line (1L) treatments in aRCC. Methods: A systematic literature review identified 24 randomized controlled trials evaluating 22 interventions in 1L treatments for aRCC. Bayesian NMAs were conducted to evaluate comparative efficacy outcomes for intention to treat (ITT) and the intermediate-/poor risk population, based on the CLEAR trial final data cutoff (31^st Jul 2022). Results: L+P had a >70% probability of providing greater OS benefit than 8 of the 12 comparators; the benefit was statistically significant against 2 treatments (interferon α-2a: hazard ratio [HR] 0.65; 95% credible interval [CrI] 0.48–0.88 and sunitinib: 0.79; 0.63–0.99). For PFS (assessed under United States Food and Drug Administration censoring rules), L+P showed a >75% probability of providing greater benefit over all available comparators, including numerical, but not statistically significant advantage over immunoncology (IO) therapies nivolumab+ipilimumab (N+I), avelumab+axitinib (A+A), nivolumab+cabozantinib (N+C) and pembrolizumab + axitinib (P+A). The benefit was significant for 13 out of 18 comparators—relative efficacy estimates ranged from HR=0.18 (95% CrI 0.08–0.40) for placebo to HR=0.51 (95% CrI 0.29–0.89) for atezolizumab + bevacizumab. For response outcomes, L+P demonstrated >90% probability of greater ORR compared with all available comparators; the benefit was statistically significant against 9 of 12 comparators—the relative odds ratio ranged from 1.85 (95% CrI 1.22–2.81) for P+A to 38.47 (95% CrI 11.94–180.19) for placebo. L+P showed statistically significant ORR benefit against IO therapies N+I and P+A, and numerical, but not statistically significant advantage over A+A and N+C. Greater than 80% probability of CR benefit was observed across 13 of 14 comparators, with statistical significance achieved against 8 comparators. L+P showed numerical, but not statistically significant advantage over all IO comparators. Comparison of the ITT population and intermediate-/poor subgroup results indicated that the benefit of L+P on PFS against comparators seen in the ITT population was generally maintained in the subgroup for those comparisons that were still feasible. Conclusions: The NMA results show that combination therapy with L+P provides a comparable OS, and a trend of improvement in PFS and response outcomes, compared with most current global standard of care IO therapies for treatment-naïve patients with aRCC.