Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT. Pembrolizumab (PEMBRO) is a monoclonal antibody targeting programmed cell death receptor 1 (PD-1). Preliminary analyses of a phase 1b/2 study of LEN + PEMBRO showed promising antitumor activity and a manageable safety profile in advanced endometrial cancer (EC). Methods: A multicenter, randomized, open-label, phase 3 study (KEYNOTE-775/E7080-G000-309; clinicaltrials.gov NCT03517449) will evaluate efficacy and safety of LEN + PEMBRO vs treatment of physician’s choice (TPC) in patients with advanced EC. Patients must be aged ≥ 18 years, have advanced EC that progressed after 1 prior platinum-based therapy, have measurable disease per RECIST v1.1, and an Eastern Cooperative Oncology Group performance status ≤ 1. Patients must have mismatch repair (MMR) status confirmed by central laboratory via immunohistochemistry on archived or fresh tumor biopsy. ~780 patients (~120 MMR-deficient; ~660 MMR-proficient) will be randomized to receive LEN 20 mg orally once daily and PEMBRO 200 mg intravenously (IV) every 3 weeks (Q3W) or TPC. Patients will be randomized first according to MMR status; MMR-proficient patients will be further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. TPC is either doxorubicin 60 mg/m² by IV Q3W or paclitaxel 80 mg/m² by 1-hour IV infusion weekly (3 weeks on/1 week off). The dual primary endpoints are progression-free survival (PFS; per RECIST v1.1 by blinded independent central review) and overall survival (OS). The PFS analysis will occur at the planned interim analysis (~363 OS events in MMR-proficient patients; ~524 PFS events), and the study will have 99% power to detect a hazard ratio (HR) of 0.55 with a 1-sided 0.0005 significance level. A final OS analysis will occur at 518 OS events, when the study will have 90% power to detect a HR of 0.75 with a 1-sided 0.0245 significance level. Secondary endpoints include objective response rate, health-related quality of life, safety and tolerability, and pharmacokinetics. Clinical trial information: NCT03517449