https://orcid.org/0000-0002-6913-9655
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Abstract
Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points.
Clinical trial registration: NCT04210115 (ClinicalTrials.gov)
Infographic
Infographic: A PDF version of this infographic is available as supplemental material.
Supplementary data
An infographic accompanies this paper at the end of the references section. To download the infographic and the supplementary data that accompanies this paper, please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fon-2020-0969
Author contributions
Conception, design or planning of the study was done by MA Shah, J Bennouna, T Doi, L Shen, K Kato, A Adenis, H Mamon, M Moehler, BC Cho, CS Shih, A Desai, and P Enzinger. Analysis of the data was performed by BC Cho and S Bordia. Acquisition of the data by MA Shah, T Doi, L Shen, M Moehler, X Fu, BC Cho and S Bordia. Interpretation of the results was done by M Moehler, BC Cho and P Bhagia. Drafting of the manuscript was done by MA Shah, M Moehler, BC Cho, S Bordia and A Desai. Critically reviewing or revising the manuscript for important intellectual content was done by MA Shah, J Bennouna, T Doi, L Shen, K Kato, A Adenis, H Mamon, M Moehler, X Fu, S Bordia, P Bhagia, CS Shih, A Desai and P Enzinger. Final approval was given by all authors.
Financial & competing interests disclosure
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. MA Shah has received research funding (to his institution) from Bristol Myers Squibb, Merck and Oncolys BioPharma. NIH funded with grant no. ROI CA228512. J Bennouna has received personal fees for advisory board and educational symposia from AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Roche and Servier. T Doi has received personal fees from AbbVie, Amgen, Astellas Pharma, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Oncolys BioPharma, Ono Pharmaceutical, Rakuten Medical, Sumitomo Dainippon, Taiho and Takeda; received grants from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck-Serono, MSD, Novartis, Pfizer, Quintiles, Sumitomo Dainippon and Taiho. L Shen has received grants from Beihai Kangcheng (Beijing) Medical Technology Co., Ltd, Beijing Xiantong Biomedical Technology Co., Ltd, Boehringer Ingelheim, Jacobio Pharmaceuticals Co., Ltd, Qilu Pharmaceutical Co., Ltd and Zaiding Pharmaceutical (Shanghai) Co., Ltd. and received consulting fees from Harbour and Merck. K Kato has received research funding from BeiGene, Bristol Myers Squibb, Merck Bio, MSD, Ono and Shionogi. A Adenis has received research funding (to his institution) from Bristol Myers Squibb, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA, and Bayer Pharmaceuticals, as well as personal fees for advisory board from Bristol Myers Squibb, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA, Merck-Serono, and Servier. H Mamon is on the advisory committee regarding this trial for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. X Fu and A Desai report nothing to disclose. M Moehler has received research funding and honoraria from MSD. BC Cho has received research funding/grants from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, GI Innovation, Janssen, MedPacto, Mogam Institute, MSD, Novartis, Ono and Yuhan; received personal fees for consulting from AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Medpacto, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan; received personal fees for scientific advisory board from Kanaph Therapeutics; is the founder of Daan Biotherapeutics; and is a stockholder of Bridgebio Therapeutics, Cyrus, Gencurix, TheraCanVac and Kanaph Therapeutics. S Bordia, P Bhagia, and CS Shih report employment with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA.P Enzinger has received personal fees from Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Medical writing and/or editorial assistance was provided by Max Chang, PhD, HC Cappelli, PhD, CMPP, and B Szente, PhD, of ApotheCom (PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA.
Ethical conduct of research
The authors state that appropriate institutional review board approval from each participating site will be obtained, and this study will follow the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent will be obtained from the participants involved prior to any study procedures.
Data sharing statement
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
Notes
ANC: Absolute neutrophil count; aPTT: Activated partial thromboplastin time; BCC: Basal cell carcinoma; EAC: Esophageal adenocarcinoma; ECOG: Eastern Cooperative Oncology Group; ESCC: Esophageal squamous cell carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; GEJC: Gastroesophageal junction cancer; INR: International normalized ratio; PT: Prothrombin time; MSI: Microsatellite instability; SCC: Squamous cell carcinoma; ULN: Upper limit of normal.