OBJECTIVES: The efficacy and safety of lenvatinib in combination with everolimus has been demonstrated in a phase 2 trial of patients with advanced or metastatic renal cell carcinoma (a/mRCC) after failure of a vascular endothelial growth factor (VEGF) inhibitor; and the combination is now approved for use in many countries around the world. The objective of this project is to understand the relative clinical efficacy of lenvatinib plus everolimus compared with other treatments currently used in this patient group.

METHODS: A systemic literature search was conducted to identify a homogeneous network of trials following prior VEGF inhibitor therapy and a targeted search extended the network to include all prior systemic therapies. The Kaplan-Meier curves were digitized and the proportional hazards assumption was examined for all included trials. Due to evidence that the hazard ratios may vary over time, parametric fractional polynomial (FP) Bayesian network meta-analyses (NMAs) were fitted to the digitized data to examine the relative efficacy in both networks.

RESULTS: The best fitting FP models for both networks confirmed that the hazard ratios varied over the first year. Three trials examining lenvatinib plus everolimus, cabozantinib, nivolumab and everolimus monotherapy following previous VEGF therapy suggest lenvatinib plus everolimus may prolong progression-free (PFS) and overall survival (OS) compared with the other treatments, although the differences were not statistically significant. Similar results were observed in the wider previous systemic therapy network where lenvatinib plus everolimus demonstrated statistical superiority on OS versus placebo and sorafenib after the first 3-6 months.

CONCLUSIONS: FP NMAs were able to provide estimates of PFS and OS which do not rely on the proportional hazards assumption and confirm lenvatinib plus everolimus is a treatment option for a/mRCC in patients who have failed prior VEGF inhibitor.