OBJECTIVES: 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 (LEN+PEM) vs. sunitinib. We conducted an indirect treatment comparison to investigate the comparative efficacy of LEN+PEM vs. other 1L treatments in aRCC.

METHODS: A systematic literature review (SLR) identified 24 RCTs evaluating 22 interventions in 1L treatments of aRCC. Bayesian network meta-analyses (NMAs) were conducted to evaluate comparative efficacy outcomes, including OS, PFS (assessed separately under US FDA and EMA censoring rules), ORR and CR. Both fixed-effects (FE) and random-effects (RE) models were run if multiple studies per comparison existed, or in case of substantial loop inconsistency or network heterogeneity.

RESULTS: For OS, LEN+PEM had a >70% probability of providing greater benefit than 9 of the 12 comparators; the benefit was statistically significant against three treatments [IFNα-2a (HR=0.59, 95% CrI 0.42-0.82), IL-2 (0.62, 0.40-0.95), and sunitinib (0.72, 0.56-0.94)]. For PFS (FDA censoring) LEN+PEM showed a > 80% probability of providing greater benefit over all available comparators; the benefit was significant 14 out of 18 comparators [relative efficacy estimates ranged from (HR=0.15,0.07-0.34, placebo) to (0.44, 0.23-0.82, nivolumab+ipilimumab)]. Similar qualitative and quantitative findings were observed for PFS (EMA censoring). For response outcomes, LEN+PEM demonstrated >90% probability of greater ORR compared to all available comparators; the benefit was statistically significant against 9 of 12 comparators [relative OR ranged from (39.06,12.06-182.91, placebo) to (1.86, 1.23-2.84, pembrolizumab+axitinib)]. Greater than 75% probability of CR benefit was observed across 13 of 14 comparators.

CONCLUSION: The NMA results show that combination therapy with LEN+PEM provides a substantial likelihood of clinically meaningful improvements in OS, PFS, and response outcomes compared with the majority of current global standard of care treatment options for treatment-naïve aRCC patients.