In the phase 1b KEYNOTE-028 study, pembrolizumab monotherapy demonstrated manageable safety and durable antitumor activity in heavily pretreated pts with PD-L1–positive advanced esophageal carcinoma. KEYNOTE-590 (ClinicalTrials.gov, NCT03189719) is a phase 3, randomized, double-blind, multicenter study of cisplatin and 5-fluorouracil plus pembrolizumab vs cisplatin and 5-fluorouracil plus placebo in pts with previously untreated advanced E/EGJ carcinoma.
Eligibility criteria are age ≥18 years; locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or metastatic Siewert type 1 adenocarcinoma of the EGJ; no prior therapy for advanced disease; measurable disease per RECIST v1.1; ECOG performance status 0/1; adequate organ function; no autoimmune disease; no active infection; and provision of tissue sample for evaluation of PD-L1 expression and gene expression profiling. Pts will be randomly assigned 1:1 to receive cisplatin 80 mg/m2 IV every 3 weeks (Q3W) (capped at 6 doses) plus 5-fluorouracil 800 mg/m2 continuous IV on days 1-5 Q3W plus pembrolizumab 200 mg IV Q3W or cisplatin 80 mg/m2 IV Q3W (capped at 6 doses) plus 5-fluorouracil 800 mg/m2 continuous IV on days 1-5 Q3W plus placebo Q3W IV. Pts will continue treatment for up to 2 years. Crossover from one treatment arm to another is not permitted. Coprimary end points are overall survival and progression-free survival per RECIST v1.1 by blinded independent central review in all pts and in pts with PD-L1–positive tumor expression (combined positive score ≥10%). Secondary end points include objective response rate per RECIST v1.1, duration of response, safety, and health-related quality of life. Response will be assessed using computed tomography (preferred) or magnetic resonance imaging every 9 weeks by central imaging review per RECIST v1.1. Adverse events (AEs) will be graded per NCI CTCAE v4.0 and monitored for at least 30 days (90 days for serious AEs) after the last dose of study treatment. Pts will be followed up for survival status. Planned enrollment is approximately 700 pts.
Clinical trial identification
NCT03189719. The study start date was July 25, 2017.
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
Medical writing and/or editorial assistance was provided by Sarita Shaevitz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.
K. Kato: Advisory board member: MSD, Ono, Beigene; Research funding: MSD, Ono, Shionogi, Merck Serono M.A. Shah: Research funding: Merck, Roche, Boston Biomedical P.C. Enzinger: Advisory board member: Merck, Astellas, Five Prime, Lilly, Celgene, Beigene J. Bennouna: Advisory board member: Roche, Boehringer Ingelheim, AstraZeneca, Shire, MSD; Honoraria: Roche, Boehringer Ingelheim, AstraZeneca, Shire, MSD. A. Adenis: Advisory board member: Bayer, BMS, Servier; Research funding: Bayer, BMS, Merck, Sanofi, Pfizer; Honoraria: Bayer, BMS, Sanofi; Travel expenses: BMS, Merck, Bayer. J-M. Sun: Advisory board member: Boehringer Ingelheim, Research funding: AstraZeneca. B.C. Cho: Advisory board member: AstraZeneca, Roche, Boehringer Ingelheim, Yuhan, BMS, MSD, Novartis Speakers\' bureau: AstraZeneca, BMS, MSD, Novartis; Research funding: Bayer, AstraZeneca, Yuhan, Novartis; Honoraria: AstraZeneca, Roche, Boehringer Ingelheim, Yuhan, BMS, MSD, Novartis. M. Ozguroglu: Advisory board member: Astellas, Janssen Honoraria: Janssen. T. Kojima: Honoraria: Oncolys Biopharma Other-Patents, Royalties; Other Intellectual Property: Ono Pharmaceutical, MSD, Shionogi Pharma, Oncolys BioPharma, Astellas Amgen BioPharama. V. Kostorov, T. Doi: Advisory board member: Novartis, MSD, Lilly Japan, Chugai Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Amgen Research funding: Taiho, Novartis, Merck Serono, Astellas Pharma, MSD, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Lilly, Sumitomo Group, Chugai Pharma, Bayer, Kyowa Hakko Kirin, Daiichi Sankyo, Celgene. Y. Zhu, P. Bhagia: Employee: Merck. S. Shah: Employee, Stock owner: Merck. All other authors have declared no conflicts of interest.