Abstract
Background: First-line treatments for metastatic clear cell renal cell carcinoma (ccRCC) combine PD-1 immune checkpoint inhibition (ICI) with CTLA-4 ICI or angiogenesis targeted therapy (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 to cabozantinib after progression on PD-1 ICI. Patients and methods: This multicenter, randomized phase II trial enrolled patients with metastatic ccRCC previously treated with 1-2 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 2 (BOP2) design was used. Results: 90 patients were randomized; 86 patients received at least 1 dose of assigned lenvatinib + everolimus (n=40) or cabozantinib (n=46). Median time from randomization to data cut-off date (August 1, 2025) was 20 months (IQR 14.9, 22.5). 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% 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-y OS probability 87.0% vs. 84.6% [95% CI 0.47-2.38] with lenvatinib + everolimus vs. 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-J o u r n a l P r e -p r o o f head comparison of contemporary second-line or later treatments after ICI, these results are relevant to treatment sequencing and inform oncology practice. A multicenter randomized phase II trial of lenvatinib + everolimus versus cabozantinib in patients with metastatic clear cell RCC (mccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI) (LenCabo) 3 (7.9%) 3 (6.8%)
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