51: A phase II study of lenvatinib plus everolimus versus cabozantinib in patients with metastatic renal cell carcinoma (mRCC) that progressed on a PD-1/PD-L1 checkpoint inhibitor (LenCabo)

Background: Combinations of immune checkpoint therapies (ICT) and angiogenesis targeted therapy (TT) are standard first-line treatment for patients with mRCC. Many patients receive cabozantinib or lenvatinib plus everolimus after progression on ICT combinations. These therapies were approved for treatment after progression on angiogenesis TT and have overlapping mechanisms of action with some first-line ICT combinations. Further, lenvatinib and cabozantinib have similar, but distinct, mechanisms of action, and the two agents have not been compared in a randomized clinical trial. We hypothesize that lenvatinib plus everolimus will produce a longer progression-free survival (PFS) compared to cabozantinib in patients with mRCC that progressed on a prior PD-1/PD-L1 checkpoint inhibitor.

Methods: This multicenter, phase II, randomized study is evaluating lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC (ccRCC) who received 1-2 prior lines of treatment in the advanced setting. The most recent treatment must include a PD-1 or PD-L1 checkpoint inhibitor. The study will enroll 90 patients and randomize in a 1:1 fashion to lenvatinib plus everolimus or cabozantinib. Patients are stratified by IMDC risk group and prior receipt of angiogenesis TT. Crossover after progression is permitted. The primary endpoint is PFS. Secondary endpoints include objective response rate, disease control rate, overall survival, health-related quality of life, and incidence of grade 3/4 adverse events. PFS will be monitored using Bayesian optimal phase 2 design, and an interim analysis will be performed at 50 patients. The study has enrolled 8 patients to date at 1 US site and will open at 2 additional US sites by February 2023. NCT05012371