A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic...

First-line treatments for metastatic clear-cell renal-cell carcinoma (ccRCC) combine programmed cell death protein 1 (PD-1) immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte associated protein 4 ICI or angiogenesis targeted therapies (TT). Upon progression, common options include cabozantinib or lenvatinib + everolimus, although these regimens have never been directly compared. We hypothesized that lenvatinib + everolimus will improve progression-free survival (PFS) compared with cabozantinib after progression on PD-1 ICI.

This multicenter, randomized phase II trial enrolled patients with metastatic ccRCC previously treated with one to two lines including PD-1 ICI. Participants received lenvatinib 18 mg/day + everolimus 5 mg/day versus cabozantinib 60 mg/day, stratified by International Metastatic RCC Database Consortium risk group and prior TT. A Bayesian optimal phase II design was used.

In total 90 patients were randomized; 86 patients received at least one dose of assigned lenvatinib + everolimus (n = 40) or cabozantinib (n = 46). Median time from randomization to data cut-off date (1 August 2025) was 20 months (interquartile range 14.9-22.5 months). A total of 60 PFS events were observed. Median PFS was 15.7 months with lenvatinib + everolimus and 10.2 months with cabozantinib [hazard ratio 0.51, 95% confidence interval (CI) 0.29-0.89, P = 0.02]. The objective response rate was 52.6% with lenvatinib + everolimus and 38.6% with cabozantinib. Overall survival (OS) data were immature and inconclusive due to a low number of events (n = 24/86; 1-year OS probability 87.0% versus 84.6% [95% CI 0.47% to 2.38%] with lenvatinib + everolimus versus cabozantinib, respectively. Discontinuation rates due to toxicity were 20% with lenvatinib + everolimus and 10.9% with cabozantinib.

In this randomized phase II trial in metastatic ccRCC that progressed on prior PD-1 ICIs, lenvatinib + everolimus significantly prolonged PFS over cabozantinib. As the first head-to-head comparison of contemporary second-line or later treatments after ICI, these results are relevant to treatment sequencing and inform oncology practice.