Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr;17(10):1143-1153.
doi: 10.2217/fon-2020-0969. Epub 2021 Feb 3.

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma

Manish A Shah  1 , Jaafar Bennouna  2 , Toshihiko Doi  3 , Lin Shen  4 , Ken Kato  5 , Antoine Adenis  6 , Harvey J Mamon  7 , Markus Moehler  8 , Xiaolong Fu  9 , Byoung Chul Cho  10 , Sonal Bordia  11 , Pooja Bhagia  11 , Chie-Schin Shih  11 , Anjali Desai  11 , Peter Enzinger  12
Affiliations

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma

Manish A Shah et al. Future Oncol. 2021 Apr.

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).

Keywords: chemotherapy; esophageal adenocarcinoma; esophageal cancer; esophageal squamous cell carcinoma; immunotherapy; pembrolizumab; radiotherapy.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. KEYNOTE-975 study design.
Definitive chemoradiotherapy consists of definitive radiotherapy + concurrent chemotherapy. †Patients in both treatment arms will receive a total of 50 Gy (FOLFOX) or 50 or 60 Gy (FP) radiotherapy over 5 weeks (6 weeks for 60 Gy). The choice of mandatory concurrent definitive chemoradiotherapy (FP with 50 Gy or 60 Gy or FOLFOX) will be at the discretion of the study site, but each investigational site must choose FP or FOLFOX and must use the same definitive chemoradiotherapy regimen for every patient at that site (i.e., a site will either be an ‘FP 50 Gy site,’ an ‘FP 60 Gy site,’ or a ‘FOLFOX site’). EAC: Esophageal adenocarcinoma; dCRT: Definitive chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group; ESCC: Esophageal squamous cell carcinoma; GEJC: Gastroesophageal junction cancer; FP: 5-Fluorouracil and cisplatin; QXW: Every ‘X’ weeks; R: Randomized.
See this image and copyright information in PMC

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018). - PubMed
    1. Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet 390(10110), 2383–2396 (2017). - PubMed
    1. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet 381(9864), 400–412 (2013). - PubMed
    1. Walker RC, Underwood TJ. Molecular pathways in the development and treatment of oesophageal cancer. Best Pract. Res. Clin. Gastroenterol. 36–37, 9–15 (2018). - PubMed
    1. Shapiro J, van Lanschot JJB, Hulshof M et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 16(9), 1090–1098 (2015). - PubMed

Publication types

MeSH terms

Substances

Associated data