Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial.

BACKGROUND:Pembrolizumab plus lenvatinib has shown antitumor activity and acceptable safety in patients with platinum-refractory urothelial carcinoma (UC). OBJECTIVE:To evaluate pembrolizumab plus either lenvatinib or placebo as first-line therapy for advanced UC in the phase 3 LEAP-011 study. DESIGN, SETTING, AND PARTICIPANTS:Patients with advanced UC who were ineligible for cisplatin-based therapy or any platinum-based chemotherapy were enrolled. INTERVENTION:Patients were randomly assigned (1:1) to pembrolizumab 200 mg intravenously every 3 wk plus either lenvatinib 20 mg or placebo orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). An external data monitoring committee (DMC) regularly reviewed safety and efficacy data every 3 mo. RESULTS AND LIMITATIONS:Between June 25, 2019 and July 21, 2021, 487 patients were allocated to receive lenvatinib plus pembrolizumab (n = 245) or placebo plus pembrolizumab (n = 242). The median time from randomization to the data cutoff date (July 26, 2021) was 12.8 mo (interquartile range, 6.9-19.3). The median PFS was 4.5 mo in the combination arm and 4.0 mo in the pembrolizumab arm (hazard ratio [HR] 0.90 [95% confidence interval {CI} 0.72-1.14]). The median OS was 11.8 mo for the combination arm and 12.9 mo for the pembrolizumab arm (HR 1.14 [95% CI 0.87-1.48]). Grade 3-5 adverse events attributed to trial treatment occurred in 123 of 241 patients (51%) treated with lenvatinib plus pembrolizumab and in 66 of 242 patients (27%) treated with placebo plus pembrolizumab. This trial was terminated earlier than initially planned based on recommendation from the DMC. CONCLUSIONS:The benefit-to-risk ratio for first-line lenvatinib plus pembrolizumab was not considered favorable versus pembrolizumab plus placebo as first-line therapy in patients with advanced UC. PATIENT SUMMARY:Lenvatinib plus pembrolizumab was not more effective than pembrolizumab plus placebo in patients with advanced urothelial carcinoma.