Background: Lenvatinib (multiple-receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptors α, c-kit, and RET) has antitumor activity in combination with pembrolizumab (anti–PD-1 inhibitor) or with chemo in advanced NSCLC. LEAP-006 (NCT03829319) evaluates first-line lenvatinib with pembrolizumab + chemo for metastatic nonsquamous NSCLC. Methods: This randomized, double-blind, 2-part, phase 3 study enrolls pts ≥18 years with histologically/cytologically confirmed metastatic, nonsquamous, treatment-naive NSCLC without sensitizing genetic aberrations. Pts receive lenvatinib 8 mg daily or matching placebo + pembrolizumab 200 mg + pemetrexed 500 mg/m² + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m² Q3W (4 cycles) followed by maintenance pembrolizumab (35 cycles) + lenvatinib/placebo + pemetrexed (no limit). In part 1 (open-label safety run-in), ~12 pts receive lenvatinib + pembrolizumab + chemo (n ≥6 in each chemo arm). If < 3 dose-limiting toxicities (DLTs; select prespecified AEs) occur in 6 pts in each arm in cycle 1, part 2 will begin enrolling. If ≥3 DLTs occur in 6 pts in each arm, enrollment in part 1 may continue with advisement by the study oversight committee. In part 2, pts are randomized 1:1 to lenvatinib or placebo + pembrolizumab + chemo, stratified by PD-L1 tumor proportion score ( < 50%/≥50%), geographic site (East Asian/other), and ECOG PS (0/1). Tumor imaging occurs at baseline and Q6W until wk 18; then Q9W until wk 54; then Q12W until verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. The primary endpoint in part 1 is safety. The primary endpoints in part 2 are PFS (RECIST v1.1 by BICR) and OS, analyzed by Kaplan-Meier method and stratified log-rank test. Secondary endpoints in part 2 are ORR and DOR (RECIST v1.1 by BICR), safety, and quality of life. Enrollment into part 1 will begin in March 2019. For part 2, approximately 714 pts will enroll in 160 sites in 17 countries. Clinical trial information: NCT03829319