KEYNOTE-495/KeyImPaCT, a randomized, phase 2, biomarker-directed 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. Clinical trial identification: NCT03516981: Trial initiation, October 1, 2018.