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Clinical Trial
. 2021 Aug 28;398(10302):759-771.
doi: 10.1016/S0140-6736(21)01234-4.

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study

Jong-Mu Sun  1 , Lin Shen  2 , Manish A Shah  3 , Peter Enzinger  4 , Antoine Adenis  5 , Toshihiko Doi  6 , Takashi Kojima  6 , Jean-Philippe Metges  7 , Zhigang Li  8 , Sung-Bae Kim  9 , Byoung Chul Cho  10 , Wasat Mansoor  11 , Shau-Hsuan Li  12 , Patrapim Sunpaweravong  13 , Maria Alsina Maqueda  14 , Eray Goekkurt  15 , Hiroki Hara  16 , Luis Antunes  17 , Christos Fountzilas  18 , Akihito Tsuji  19 , Victor Castro Oliden  20 , Qi Liu  21 , Sukrut Shah  21 , Pooja Bhagia  21 , Ken Kato  22 ; KEYNOTE-590 Investigators
Affiliations
Clinical Trial

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study

Jong-Mu Sun et al. Lancet. .

Erratum in

  • Department of Error.
    [No authors listed] [No authors listed] Lancet. 2021 Nov 20;398(10314):1874. doi: 10.1016/S0140-6736(21)02487-9. Lancet. 2021. PMID: 34801105 No abstract available.

Abstract

Background: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer.

Methods: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment.

Findings: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group.

Interpretation: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population.

Funding: Merck Sharp & Dohme.

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Conflict of interest statement

Declaration of interests J-MS reports research funding to the institution by Merck Sharp & Dohme (MSD; a subsidiary of Merck), AstraZeneca, and Ono Pharmaceuticals, during the conduct of the study. LS reports research funding to the institution by MSD, grants from Beijing Xiantong Biomedical Technology, Qily Pharmaceutical, Zaiding Pharmaceutical, Jacobio Pharmaceuticals, and Beihai Kangcheng Medical Technology, and consulting fees from HARBOUR and Merck, during the conduct of the study. MAS reports funding to the institution from MSD, Bristol Myers Squibb (BMS), and Oncolys BioPharma, during the conduct of the study. PE reports funding to the institution from MSD, during the conduct of the study, and personal fees from MSD, AstraZeneca, Celgene, Daiichi Sankyo, Five Prime, Lilly, Loxo, Taiho, Takeda, and Zymeworks, outside of the submitted work. AA reports funding to the institution from MSD, BMS, and Bayer Pharmaceuticals, during the conduct of the study, and personal fees from MSD and BMS, and personal fees for advisory role from Merck Serono and Servier, outside of the submitted work. TD reports funding to the institution from MSD, Daiichi Sankyo, Sumitomo Dainippon, AbbVie, Novartis, Boehringer Ingelheim, Taiho Pharmaceutical, Merck Serono, BMS, Pfizer, Lilly, Kyowa Hakko, Kirin, and IQVIA, during the conduct of the study, and personal fees for consulting or advisory role from MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer, Boehringer Ingelheim, Rakuten Medical, and BMS, and honoraria from Ono Pharmaceutical, Astellas Pharma, Oncolys BioPharma, Taiho Pharmaceutical, and Otsuka, outside of the submitted work. TK reports funding to the institution from MSD, Ono Pharmaceutical, Shionogi, Astellas Amgen Bio Pharma, and Taiho Pharmaceutical, during the conduct of the study, and personal fees from MSD, Ono Pharmaceutical, Merck, Astellas Pharma, BMS, and Oncolys BioPharma, outside of the submitted work. J-PM reports funding to the institution from MSD, during the conduct of the study, and honoraria from MSD, Bayer, and BMS, outside of the submitted work. ZL reports funding to the institution from MSD, during the conduct of the study. S-BK reports funding to the institution from MSD, Novartis, and Sanofi-Genzyme, during the conduct of the study, and personal fees for consulting or advisory role from Dae Hwa Pharmaceutical, ISU Abxis, and Daiichi-Sankyo, outside of the submitted work. BCC reports funding to the institution from MSD, Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, AbbVie, Medpacto, G Innovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence, fees for consulting or advisory role from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint Medicines, KANAPH Therapeutic, Brigebio Therapeutics, Cyrus Therapeutics, and Guardant Health, stock ownership in TheraCanVac, Gencurix, Bridgebio Therapeutics, KANAPH Therapeutic, Cyrus Therapeutics, and Interpark Bio Convergence, personal fees for Board of Directorship from Gencurix and Interpark Bio Convergence, royalties from Champions Oncology, and is the founder of DAAN Biotherapeutics, outside of the submitted work. MAM reports funding to the institution from MSD, during the conduct of the study, and consultancy for MSD, BMS, Servier, and Lilly, and honoraria from BMS, Servier, and Amgen, outside of the submitted work. EG reports funding to the institution from MSD, during the conduct of the study, and personal fees from MSD, BMS, Servier, and Roche, outside of the submitted work. HH reports funding to the institution from MSD, during the conduct of the study, and grants from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Merck Biopharma, MSD, Taiho, Chugai, Eisai, LSK BioPharma, Incyte, Pfizer, Boehringer Ingelheim, Beigene, Ono, BMS, and Astellas, and personal fees from Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, Merck Biopharma, MSD, Taiho, Chugai, Ono, BMS, Yakult Honsha, Sanofi, Takeda, and Kyowa Hakko Kirin, outside of the submitted work. CF reports funding to the institution from MSD, during the conduct of the study, and grants and non-financial support from National Comprehensive Cancer Network, Taiho Oncology, Pfizer, and AstraZeneca, outside of the submitted work. AT reports funding to the institution from MSD, during the conduct of the study, and grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Merck Biopharma, Takeda Pharmaceutical, Sanofi, Ono Pharmaceutical, Kyowa Hakko Kirin, Eisai, Toray Medical, Daiichi Sankyo, Bayer Yakuhin, Shionogi, Pfizer, and Yakult Honsha, and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, BMS, Merck Biopharma, Takeda Pharmaceutical, and Sanofi, outside of the submitted work. WM, S-HL, PS, LA, and VCO report funding to the institution from MSD, during the conduct of the study. QL, SS, and PB are employees and hold stock in MSD. KK reports funding to the institution from MSD, during the conduct of the study, and research funding from Ono, BMS, Beigene, Shionogi, Merck Biopharma, Oncolys Biopharma, and Chugai, outside of the submitted work.

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