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

Manish A Shah, Jaafar Bennouna, Toshihiko Doi, Lin Shen, Ken Kato, Antoine Adenis, Harvey J Mamon, Markus Moehler, Xiaolong Fu, Byoung Chul Cho, Sonal Bordia, Pooja Bhagia, Chie-Schin Shih, Anjali Desai, Peter Enzinger, Manish A Shah, Jaafar Bennouna, Toshihiko Doi, Lin Shen, Ken Kato, Antoine Adenis, Harvey J Mamon, Markus Moehler, Xiaolong Fu, Byoung Chul Cho, Sonal Bordia, Pooja Bhagia, Chie-Schin Shih, Anjali Desai, Peter Enzinger

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.

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.. KEYNOTE-975 study design.
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.

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    2. • The multicohort, Phase Ib KEYNOTE-028 study evaluated patients with previously treated PD-L1+ esophageal carcinoma treated with pembrolizumab monotherapy.

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    2. • The efficacy and safety of pembrolizumab were investigated in the open-label, single-arm, Phase II KEYNOTE-180 study in patients with esophageal cancer that progressed after two or more lines of therapy.

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    2. • The open-label, Phase III KEYNOTE-181 study evaluated patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus that progressed after one prior therapy who were randomly assigned to receive pembrolizumab or investigator’s choice of chemotherapy.

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    2. • The randomized, double-blind, placebo-controlled, Phase III KEYNOTE-590 study investigated pembrolizumab plus chemotherapy as first-line treatment in patients with advanced esophageal or esophagogastric junction cancer.

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Source: PubMed

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