4799 - KEYNOTE-495/KeyImPaCT: A Randomized, Biomarker-Directed, Phase 2 Trial of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (NSCLC)

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—TMB^lowGEP^low, TMB^highGEP^low, TMB^lowGEP^high, and TMB^highGEP^high—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.

Editorial acknowledgement

Holly C. Cappelli, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

M. Gutierrez: Advisory / Consultancy: Eli Lilly, Foundation One, Essanex, Guardant 360; Speaker Bureau / Expert testimony: Merck, BMS. M.D. Hellmann: Advisory / Consultancy: Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs; Shareholder / Stockholder / Stock options: Shattuck Labs; Research grant / Funding (institution): BMS; Travel / Accommodation / Expenses: AstraZeneca, BMS; Non-remunerated activity/ies, A patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx.: MSK. M.A. Gubens: Advisory / Consultancy: AbbVie, ARIAD, AstraZeneca, BMS, Roche/Genentech, Heron, Mersana, Novartis, Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene, Merck, Novartis; Research grant / Funding (institution): OncoMed, Roche. C. Aggarwal: Advisory / Consultancy: BMS, Celgene, Roche/Genentech, AstraZeneca. D.S.W. Tan: Honoraria (self): Novartis, Bayer, Boehringer Ingelheim, AstraZeneca, BMS, Roche, Takeda, Pfizer; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, GSK, Pfizer; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda; Advisory / Consultancy: Blue Print Medicines, Celgene, Guardant Health. J.C. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, BMS, Ono Pharmaceuticals ; Advisory / Consultancy: Merck Serono, Celgene, Merrimack, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals Blueprint Medicines. E.B. Garon: Research grant / Funding (self), Clinical trial funding: Merck, AstraZeneca, BMS. A. Basso: Full / Part-time employment: Merck . H. Ma: Full / Part-time employment: Merck . L. Fong: Research grant / Funding (self): Merck . A. Snyder: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck . J. Yuan: Full / Part-time employment: Merck . R.S. Herbst: Advisory / Consultancy: AbbVie, AstraZeneca, Biodesix, BMS, Eli Lilly, EMD Serano, Roche/Genentech, Heat Biologics, Junshi, Loxo Oncology Merck, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum, Symphogen, Tesaro ; Research grant / Funding (self): AstraZeneca, Eli Lilly, Merck; Advisory / Consultancy, Scientific Advisory Boards: Neon Therapeutics, Infinity Pharmaceuticals, NextCure; Officer / Board of Directors: Junshi Pharmaceuticals. All other authors have declared no conflicts of interest.