Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial (NCT03516981) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group-sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cell?inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMB^lowGEP^low, TMB^highGEP^low, TMB^lowGEP^high, and TMB^highGEP^high. Within each group, patients will be randomly assigned to receive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (anti?LAG-3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981