NCT03221426 · CITED IN SOURCE DOCUMENTS

Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants With Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-585/KEYNOTE-585)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2026-03-09

The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in the neoadjuvant (prior to surgery) or adjuvant (after surgery) treatment of previously untreated adults with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The primary study hypotheses are that: * Neoadjuvant and adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in terms of Event-free Survival (EFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), and * Neoadjuvant pembrolizumab plus chemotherapy is superior to neoadjuvant placebo plus chemotherapy in terms of rate of Pathological Complete Response (pathCR) at the time of surgery. With Amendment 10, upon study completion, participants will be discontinued and may be enrolled in an extension study.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms

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outcome · POSTED

Pathological Complete Response (pathCR) Rate - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms

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outcome · POSTED

Overall Survival (OS) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms

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outcome · POSTED

Number of Participants Who Experienced One or More Adverse Events (AEs) - Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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outcome · POSTED

Number of Participants Who Discontinued Study Treatment Due to an AE - Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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outcome · POSTED

Number of Participants Who Experienced One or More Adverse Events (AEs) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms Separately and in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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outcome · POSTED

Number of Participants Who Discontinued Study Treatment Due to an AE - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms Separately and in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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outcome · POSTED

Disease-free Survival (DFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms

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outcome · POSTED

Overall Survival (OS) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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outcome · POSTED

Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Has previously untreated localized gastric or GEJ adenocarcinoma as defined by T3 or greater primary lesion or the presence of any positive nodes - N+ (clinical nodes) without evidence of metastatic disease. * Plans to proceed to surgery following pre-operative chemotherapy based on standard staging studies per local practice. * Is willing to provide tissue from a tumor lesion at baseline and at time of surgery. * Has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 within 3 days prior to the first dose of study treatment. * Has adequate organ function. * Male participants of childbearing potential must agree to use an adequate method of contraception for the course of the study through 180 days after the last dose of chemotherapy. * Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater. * Has life expectancy of greater than 6 months. Exclusion Criteria: * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. * Has an active infection requiring systemic therapy. * Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. * Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], tumor necrosis factor receptor superfamily member 4 \[OX-40\], necrosis factor receptor superfamily member 9 \[CD137\]) or has previously participated in a MSD pembrolizumab (MK-3475) clinical study. * Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior the first dose of study treatment. * Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded. * Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients, or to any of the study chemotherapy agents and/or to any of their excipients. * Has an active autoimmune disease that has required systemic treatment in past 2 years. * Has a known history of human immunodeficiency virus (HIV) infection. * Has a known history of Hepatitis B or known active Hepatitis C virus infection. * Has a known history of active tuberculosis (TB). * Female participants who are pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater. * Male participants who are expecting to father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of chemotherapy. * Has had an allogenic tissue/solid organ transplant. * Has received a live vaccine within 30 days prior to the first dose of study treatment.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
XP=cisplatin+capecitabine and FP=cisplatin+5-fluorouracil. Neoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets twice each day (BID) on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m\^2 continuous IV infusion on Days 1 to 5 of each 3-week cycle. Adjuvant: 4 to 10 weeks post-surgery, participants receive 3 cycles of pembrolizumab 200 mg IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 continuous IV infusion on Days 1 to 5 of each 3-week cycle, followed by pembrolizumab monotherapy 200 mg IV infusion on Day 1 Q3W for up to 11 additional cycles.
intervention Names
Biological: Pembrolizumab
Drug: Cisplatin
Drug: Capecitabine
Drug: 5-fluorouracil
label
Pembrolizumab + XP/FP
type
EXPERIMENTAL
description
Neoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 via continuous IV infusion on Days 1 to 5 of each 3-week cycle. Adjuvant: 4 to 10 weeks post-surgery, participants receive 3 cycles of placebo via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 via continuous IV infusion on Days 1 to 5 of each 3-week cycle, followed by placebo monotherapy via IV infusion on Day 1 Q3W for up to 11 additional cycles.
intervention Names
Drug: Placebo
Drug: Cisplatin
Drug: Capecitabine
Drug: 5-fluorouracil
label
Placebo + XP/FP
type
PLACEBO_COMPARATOR
description
FLOT=docetaxel+oxaliplatin+5FU+leucovorin (calcium folinate). Neoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin (calcium folinate) 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations). Adjuvant: 4 to 10 weeks postsurgery, participants receive 3 cycles of pembrolizumab 200 mg via IV infusion Day 1 Q3W PLUS docetaxel 50 mg/m\^2, oxaliplatin 85 mg/m\^2, 5FU 2600 mg/m\^2, and leucovorin 200 mg/m\^2 Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations), followed by pembrolizumab monotherapy 200 mg via IV infusion on Day 1 Q3W for up to 11 additional cycles.
intervention Names
Biological: Pembrolizumab
Drug: 5-fluorouracil
Drug: Docetaxel
Drug: Oxaliplatin
Drug: Leucovorin
label
Pembrolizumab+FLOT Cohort
type
EXPERIMENTAL
description
Neoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations). Adjuvant: 4 to 10 weeks postsurgery, participants receive 3 cycles of placebo via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations), followed by placebo monotherapy via IV infusion on Day 1 Q3W for up to 11 additional cycles.
intervention Names
Drug: Placebo
Drug: 5-fluorouracil
Drug: Docetaxel
Drug: Oxaliplatin
Drug: Leucovorin
label
Placebo+FLOT Cohort
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Pembrolizumab + XP/FP
Pembrolizumab+FLOT Cohort
description
IV infusion
name
Pembrolizumab
other Names
MK-3475
KEYTRUDA®
type
BIOLOGICAL
arm Group Labels
Placebo + XP/FP
Placebo+FLOT Cohort
description
IV infusion
name
Placebo
other Names
Normal saline solution
type
DRUG
arm Group Labels
Pembrolizumab + XP/FP
Placebo + XP/FP
description
IV infusion
name
Cisplatin
other Names
PLATINOL®
type
DRUG
arm Group Labels
Pembrolizumab + XP/FP
Placebo + XP/FP
description
Oral tablets
name
Capecitabine
other Names
XELODA®
type
DRUG
arm Group Labels
Pembrolizumab + XP/FP
Pembrolizumab+FLOT Cohort
Placebo + XP/FP
Placebo+FLOT Cohort
description
IV infusion
name
5-fluorouracil
other Names
ADRUCIL®
5FU
type
DRUG
arm Group Labels
Pembrolizumab+FLOT Cohort
Placebo+FLOT Cohort
description
IV infusion
name
Docetaxel
other Names
TAXOTERE®
type
DRUG
arm Group Labels
Pembrolizumab+FLOT Cohort
Placebo+FLOT Cohort
description
IV infusion
name
Oxaliplatin
other Names
ELOXATIN®
type
DRUG
arm Group Labels
Pembrolizumab+FLOT Cohort
Placebo+FLOT Cohort
description
IV infusion
name
Leucovorin
other Names
WELLCOVORIN®
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
masking Description: Double-blind study
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 1007
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS was based on RECIST 1.1 as assessed by the investigator and was defined as the time from randomization to the first of the following events: radiographic disease progression per RECIST 1.1; local or distant recurrence as assessed by computer tomography (CT) scan or biopsy if indicated (for participants who were disease free after surgery); clinical progression as evidenced by peritoneal carcinomatosis confirmed by preoperative laparoscopy or laparotomy (for participants who were confirmed to be free of peritoneal involvement by laparoscopy at screening); or death due to any cause. A second primary malignancy, or radiographic progressive disease (PD) during the neoadjuvant phase that does not preclude successful surgery (i.e., disease free after surgery), were not considered EFS events.
measure
Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms
time Frame
Up to approximately 75 months
description
PathCR rate was defined as the percentage of participants having a pathCR based on central review. pathCR was defined as no invasive disease within an entirely submitted and evaluated gross lesion, and histologically negative nodes. The percentage of participants having pathCR was presented for the Pembrolizumab+XP/FP and Placebo+XP/FP treatment arms.
measure
Pathological Complete Response (pathCR) Rate - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms
time Frame
Up to approximately 9 weeks following completion of neoadjuvant treatment (up to Study Week 18)
description
OS was defined as the time from randomization to death due to any cause. OS was presented for the Pembrolizumab+XP/FP and Placebo+XP/FP treatment arms.
measure
Overall Survival (OS) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms
time Frame
Up to approximately 75 months
description
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE was presented for the Pembrolizumab+FLOT and Placebo+FLOT Cohorts.
measure
Number of Participants Who Experienced One or More Adverse Events (AEs) - Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 70 months
description
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued study treatment due to an AE was presented for the Pembrolizumab+FLOT and Placebo+FLOT Cohorts.
measure
Number of Participants Who Discontinued Study Treatment Due to an AE - Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 17 months

secondary Outcomes

description
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced at least one AE was presented for the Pembrolizumab+XP/FP and Placebo+XP/FP treatment arms separately and in combination with the Pembrolizumab+FLOT and Placebo+FLOT Cohorts.
measure
Number of Participants Who Experienced One or More Adverse Events (AEs) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms Separately and in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 89 months
description
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued study treatment due to an AE was presented for the Pembrolizumab+XP/FP and Placebo+XP/FP treatment arms separately and in combination with the Pembrolizumab+FLOT and Placebo+FLOT Cohorts.
measure
Number of Participants Who Discontinued Study Treatment Due to an AE - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms Separately and in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 17 months
description
DFS was defined as the time from post-surgery baseline scan until the first occurrence of local or distant recurrence or death from any cause and was based on RECIST 1.1 as assessed by the investigator.
measure
Disease-free Survival (DFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms
time Frame
Up to approximately 75 months
description
OS was defined as the time from randomization to death due to any cause. OS was presented for the Pembrolizumab+XP/FP and Placebo+XP/FP treatment arms in combination with the Pembrolizumab+FLOT and Placebo+FLOT Cohorts.
measure
Overall Survival (OS) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 75 months
description
EFS was based on RECIST 1.1 as assessed by the investigator and was defined as the time from randomization to the first of the following events: radiographic disease progression per RECIST 1.1; local or distant recurrence as assessed by CT scan or biopsy if indicated (for participants who were disease free after surgery); clinical progression as evidenced by peritoneal carcinomatosis confirmed by preoperative laparoscopy or laparotomy (for participants who were confirmed to be free of peritoneal involvement by laparoscopy at screening); or death due to any cause. A second primary malignancy, or radiographic progressive disease (PD) during the neoadjuvant phase that does not preclude successful surgery (i.e., disease free after surgery), were not considered EFS events.
measure
Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+XP/FP and Placebo+XP/FP Treatment Arms in Combination With the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
time Frame
Up to approximately 75 months

Full study description

brief Summary: The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in the neoadjuvant (prior to surgery) or adjuvant (after surgery) treatment of previously untreated adults with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The primary study hypotheses are that: * Neoadjuvant and adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in terms of Event-free Survival (EFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), and * Neoadjuvant pembrolizumab plus chemotherapy is superior to neoadjuvant placebo plus chemotherapy in terms of rate of Pathological Complete Response (pathCR) at the time of surgery. With Amendment 10, upon study completion, participants will be discontinued and may be enrolled in an extension study.

Source references

references

citation
Shitara K, Rha SY, Wyrwicz LS, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, Al-Batran SE, Yoshikawa T, Yanez P, Dib Bartolomeo M, Lonardi S, Tabernero J, Van Cutsem E, Janjigian YY, Oh DY, Xu J, Fang X, Shih CS, Bhagia P, Bang YJ; KEYNOTE-585 investigators. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 2024 Feb;25(2):212-224. doi: 10.1016/S1470-2045(23)00541-7. Epub 2023 Dec 19.
pmid
38134948
type
RESULT
citation
Shitara K, Rha SY, Wyrwicz L, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, Al-Batran SE, Yoshikawa T, Yanez P, Pietrantonio F, Lonardi S, Fang X, Guan Y, Valderrama A, Leconte P, Bhagia P, Bang YJ; KEYNOTE-585 Investigators. Pembrolizumab Plus Chemotherapy Versus Chemotherapy as Perioperative Therapy in Locally Advanced Gastric and Gastroesophageal Junction Cancer: Final Analysis of the Randomized, Phase III KEYNOTE-585 Study. J Clin Oncol. 2025 Oct 10;43(29):3152-3159. doi: 10.1200/JCO-25-00486. Epub 2025 Aug 19.
pmid
40829093
type
DERIVED
citation
Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore). 2022 May 27;101(21):e29304. doi: 10.1097/MD.0000000000029304.
pmid
35623069
type
DERIVED
citation
Bang YJ, Van Cutsem E, Fuchs CS, Ohtsu A, Tabernero J, Ilson DH, Hyung WJ, Strong VE, Goetze TO, Yoshikawa T, Tang LH, Hwang PMT, Webb N, Adelberg D, Shitara K. KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol. 2019 Mar;15(9):943-952. doi: 10.2217/fon-2018-0581. Epub 2019 Feb 19.
pmid
30777447
type
DERIVED