Background: Pembrolizumab is approved for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥1%. The multireceptor tyrosine kinase inhibitor lenvatinib enhances antitumor activity of PD-1 inhibitors in vitro and has shown clinical activity with pembrolizumab in patients with metastatic NSCLC (NCT02501096). LEAP-008 (NCT03976375) evaluates the efficacy and safety of second/subsequent-line pembrolizumab plus lenvatinib vs docetaxel in patients with previously treated metastatic NSCLC refractory to anti-PD-(L)1 therapy and platinum-doublet chemotherapy. Methods: In this randomized, global, open-label, active-controlled study, patients (n = 405) with metastatic NSCLC who progressed after platinum-doublet chemotherapy and anti-PD-(L)1 therapy are randomized 4:4:1 to pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily (Arm 1, n = 180), docetaxel 75 mg/m2 Q3W (Arm 2, n = 180), or lenvatinib 24 mg once daily (Arm 3, n = 45). Patients are stratified by anti-PD-(L)1 therapy sequencing (immediate prior therapy vs not immediate prior therapy), PD-L1 TPS (<50% vs ≥50%), and Eastern Cooperative Oncology Group performance status (0 vs 1). Treatment continues until PD, unacceptable AEs, concurrent illness preventing study drug administration, investigator decision, or patient withdrawal. Blood pressure is regularly assessed and, if elevated, anti-hypertensive medications are administered and lenvatinib may be withheld and resumed, with or without dose reduction, or discontinued per protocol. Imaging is assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Q6W from randomization until week 36, then Q9W until week 54, then Q12W until PD or start of new anti-cancer regimen. Dual primary outcomes are OS and PFS (RECIST version 1.1 by BICR). Secondary outcomes include ORR (RECIST version 1.1 by BICR), duration of response (RECIST version 1.1 by BICR), safety (AEs graded by National Cancer Institute Common Terminology for Adverse Events version 4.0), and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Lung Cancer Module 13). PFS and OS will be analyzed by the Kaplan-Meier method and stratified log-rank test; differences in ORR will be analyzed by the Miettinen and Nurminen method.

Citation Format: Natasha B. Leighl, Rina Hui, Delvys Rodríguez-Abreu, Makoto Nishio, Matthew D. Hellmann, Chooi Lee, Xuan Deng, Debra Kush, Hossein Borghaei, Justin Gainor. Pembrolizumab plus lenvatinib vs docetaxel in patients with previously treated metastatic non-small-cell lung cancer (NSCLC) and PD after platinum-doublet chemotherapy and immunotherapy: Phase 3, randomized, open-label LEAP-008 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT289.