Abstract CT227: KEYNOTE-495/KeyImPaCT: Phase II biomarker-directed precision oncology study of pembrolizumab-based combination therapy for non-small cell lung cancer
Authors: Gutierrez Martin , Hellmann Matthew D. , Gubens Matthew , Aggarwal Charu , Tan Daniel Shao Weng , Felip Enriqueta , Chiu Joanne Wing Yan , Lee Jong-Seok , Yang James Chih-Hsin , Garon Edward , Basso Andrea D. , Ma Hua , Fong Lawrence , Snyder Alex , Yuan Jianda , Herbst Roy S. 
Published: August 2019

Abstract
Background: Immune checkpoint-based therapy has revolutionized the care of patients with NSCLC. Pembrolizumab-based combination therapy aims to improve clinical outcomes over pembrolizumab monotherapy. Identification of biomarkers associated with improved response to different combination therapies may improve overall outcomes and yield a more precise approach to the use of immunotherapies in NSCLC. To test the clinical usefulness of a biomarker-informed pembrolizumab-based combination therapy, this phase 2 KEYNOTE-495 trial (NCT03516981) will be carried out in patients with treatment-naive, advanced NSCLC.
Methods: KEYNOTE-495 is a randomized, multicenter, open-label, Phase II trial. Tumor tissue from patients with treatment-naive, advanced NSCLC 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 the results of this biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti-LAG-3) or lenvatinib. This is a group-sequential, adaptive randomization trial. Response will be assessed by tumor imaging every 9 weeks for the first year, then 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. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment or before initiation of a new anticancer treatment, whichever occurs first. Treatment arms may be terminated during the interim analysis because of safety, prespecified futility criteria, or both. The 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 and will continue until ~192 patients are randomly assigned within each biomarker-defined group to determine optimal treatment for each subgroup.
Citation Format: Martin Gutierrez, Matthew D. Hellmann, Matthew Gubens, Charu Aggarwal, Daniel Shao Weng Tan, Enriqueta Felip, Joanne Wing Yan Chiu, Jong-Seok Lee, James Chih-Hsin Yang, Edward Garon, Andrea D. Basso, Hua Ma, Lawrence Fong, Alex Snyder, Jianda Yuan, Roy S. Herbst. KEYNOTE-495/KeyImPaCT: Phase II biomarker-directed precision oncology study of pembrolizumab-based combination therapy for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT227.