KEYNOTE-495/KeyImPaCT: A randomized, biomarker-directed, phase II trial of pembrolizumab-based therapy for non–small cell lung cancer (NSCLC)

Abstract

Background: KEYNOTE‐495 is a randomized, open‐label, phase II trial (NCT03516981) evaluating the clinical activity and safety of pembrolizumab (pembro)‐based combination (combo) therapy in patients (pts) with treatment‐naive, advanced NSCLC in biomarker‐defined response groups. This biomarker‐based approach is based on 2 validated, independent, next‐generation biomarkers (T cell‐ inflamed gene expression profile [GEP] and tumor mutational burden [TMB]) and can help determine the differential efficacy of pembro‐based combo therapy, based on the composite biomarker profile, and inform precision immunotherapy in the future. Trial design: In this group‐sequential, adaptive randomized trial, pts (N∼288) receive pembro 200 mg Q3W intravenously (IV) combined with MK‐4280 (anti‐LAG‐3) 200 mg Q3W IV, lenvatinib (lenv) 20 mg PO QD, or MK‐1308 (anti‐CTLA‐4) 25 mg Q6W IV for 35 cycles (∼2 years); pts in the lenv arm may receive lenv monotherapy until disease progression or toxicity. After biomarker screening, pts are assigned to 1 of 4 groups‐TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh‐ then randomized to 1 of 3 pembro‐based regimens; adaptive design elements are used to adjust randomization based on objective responses. Eligible pts are ≥18 years of age with 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. Response is assessed by imaging Q9W for the first year and Q12W thereafter using RECIST v1.1. Primary end point is investigator‐assessed objective response rate (RECIST v1.1). Secondary end points are progression‐free survival, overall survival, and safety. Multiple interim analyses may be performed given the group‐sequential design. Enrollment is ongoing.