Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With TS-1+Cisplatin or TS-1+Oxaliplatin as First Line Chemotherapy in Gastric Cancer (MK-3475-659/KEYNOTE-659)

A Phase IIb, Clinical Trial to Study the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With TS-1+Cisplatin or TS-1+Oxaliplatin as a First Line Chemotherapy in Participants With Advanced or Recurrent Gastric Cancer (KEYNOTE-659)

The purpose of this study is to estimate objective response rates (ORRs) of pembrolizumab + oxaliplatin + TS-1 and pembrolizumab + cisplatin + TS-1, as first-line treatment for gastric cancer in programmed death-ligand 1 (PD-L1) positive, human epidermal growth factor receptor 2 (HER2/neu)-negative participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Biological: Pembrolizumab; Drug: TS-1; Drug: Cisplatin

Detailed Description

Approximately 45 participants will be assigned to pembrolizumab + oxaliplatin + TS-1 combination therapy (Cohort 1) first, and then 45 participants will be assigned to pembrolizumab + cisplatin + TS-1 combination therapy (Cohort 2).

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 260-8717
    • Chiba Cancer Center ( Site 0012)
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center ( Site 0017)
  • Fukuoka, Japan, 812-8582
    • Kyushu University Hospital ( Site 0014)
  • Gifu, Japan, 501-1194
    • Gifu University Hospital ( Site 0021)
  • Kochi, Japan, 781-8555
    • Kochi Health Sciences Center ( Site 0022)
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital ( Site 0002)
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute ( Site 0011)
  • Tokyo, Japan, 104-0045
    • National Cancer Center Hospital ( Site 0025)
  • Tokyo, Japan, 113-8677
    • Tokyo Metropolitan Komagome Hospital ( Site 0008)
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR ( Site 0007)
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East ( Site 0001)
  • Ehime
    • Matsuyama, Ehime, Japan, 791-0280
      • National Hospital Organization Shikoku Cancer Center ( Site 0024)
  • Gunma
    • Ohta, Gunma, Japan, 373-8550
      • Gunma Prefectural Cancer Center ( Site 0005)
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital ( Site 0006)
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Hyogo Cancer Center ( Site 0016)
    • Kobe, Hyogo, Japan, 650-0047
      • Kobe City Medical Center General Hospital ( Site 0015)
  • Ibaraki
    • Kasama, Ibaraki, Japan, 309-1793
      • Ibaraki Prefectural Central Hospital ( Site 0018)
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0375
      • Kitasato University Hospital ( Site 0019)
    • Yokohama, Kanagawa, Japan, 241-8515
      • Kanagawa Cancer Center ( Site 0003)
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital ( Site 0023)
  • Osaka
    • Osakasayama, Osaka, Japan, 589-8511
      • Kindai University Hospital ( Site 0013)
    • Suita, Osaka, Japan, 565-0871
      • Osaka University Hospital ( Site 0010)
  • Saitama
    • Kitaadachi-gun, Saitama, Japan, 362-0806
      • Saitama Cancer Center ( Site 0004)
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 411-8777
      • Shizuoka Cancer Center Hospital and Research Institute ( Site 0020)
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0498
      • Jichi Medical University Hospital ( Site 0009)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma
• Has a PD-L1 positive tumor as determined by immunohistochemistry (IHC) at a central laboratory
• Has measurable disease as defined by RECIST 1.1 as determined by investigator assessment. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at the timing of enrollment
• Participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication
• Has adequate organ function

Exclusion Criteria:

• Has squamous cell or undifferentiated gastric cancer
• HER2-positive status
• Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation
• Has received prior therapy with a platinum-based anti-cancer drug
• Has had major surgery, open biopsy or significant traumatic injury within 28 days prior to enrollment, or anticipation of the need for major surgery during the course of study treatment
• Has had radiotherapy within 14 days of enrollment
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has any active infection requiring systemic therapy
• Will be on flucytosine at the time of enrollment
• Has grade ≥ 2 peripheral sensory neuropathy
• Has poorly controlled diarrhea (e.g., watery stool, uncontrollable bowel movement with drugs, grade ≥ 2 and number of defecations, ≥ 5/day)
• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 weeks prior to enrollment
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
• Has known history of human immunodeficiency virus (HIV) [HIV1/2 antibodies]
• Has a known history of Hepatitis B
• Has received live vaccine within 30 days of the planned start of study therapy
• Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of trial treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1); Participants receive pembrolizumab 200 mg every 3 weeks (Q3W) plus oxaliplatin 130 mg/m^2 Q3W by intravenous (IV) infusion plus TS-1 twice daily (BID) by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course, and will continue for up to ~3 years.	Drug: Oxaliplatin; 130 mg/m^2 Q3W on Day 1 by IV infusion; Biological: Pembrolizumab; 200 mg Q3W on Day 1 by IV infusion; Other Names: MK-3475; Drug: TS-1; 40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14
Experimental: Pembrolizumab + Cisplatin +TS-1 (Cohort 2); Participants receive pembrolizumab 200 mg Q3W plus cisplatin 60 mg/m^2 Q3W by IV infusion plus TS-1 BID by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course, and will continue for up to ~3 years.	Biological: Pembrolizumab; 200 mg Q3W on Day 1 by IV infusion; Other Names: MK-3475; Drug: TS-1; 40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14; Drug: Cisplatin; 60 mg/m^2 Q3W on Day 1 by IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR)	For the primary efficacy analysis, ORR was defined as the percentage of participants who have a best response of complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) per RECIST 1.1 as assessed by BICR.	Up to ~36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR According to Immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) Assessed by BICR	For the secondary efficacy analysis, ORR was defined as the percentage of participants whose best response based on imaging is CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD) according to iRECIST as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.	Up to ~36 months
Duration of Response (DOR) According to RECIST 1.1 Assessed by BICR	For participants who demonstrated complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the SOD of target lesions) according to RECIST 1.1 as assessed by BICR, DOR was defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of progressive disease (PD, ≥20% increase in the SOD of target lesions) or death from any cause, whichever came first. DOR was censored at the last tumor assessment date if a responder did not have PD or death.	Up to ~36 months
DOR According to iRECIST Assessed by BICR	For participants who demonstrated complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the SOD of target lesions) according to iRECIST as assessed by BICR, DOR was defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of progressive disease (PD, ≥20% increase in the SOD of target lesions) or death from any cause, whichever came first. DOR was censored at the last tumor assessment date if a responder did not have PD or death. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.	Up to ~36 months
Disease Control Rate (DCR) According to RECIST 1.1 Assessed by BICR	DCR was defined as the percentage of participants in the analysis population who have complete response (CR, disappearance of all target lesions), partial response (PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD), or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD, ≥20% increase in the SOD of target lesions]). Responses are according to RECIST 1.1 as assessed by BICR.	Up to ~36 months
DCR According to iRECIST 1.1 Assessed by BICR	DCR was defined as the percentage of participants in the analysis population who have CR (disappearance of all target lesions), PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD), or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [≥20% increase in the SOD of target lesions]). Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.	Up to ~36 months
Time to Response (TTR) According to RECIST 1.1 Assessed by BICR	TTR was defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD). Responses are according to RECIST 1.1 as assessed by BICR.	Up to ~36 months
TTR According to iRECIST 1.1 Assessed by BICR	TTR was defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD). Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.	Up to ~36 months
Progression-free Survival (PFS) According to RECIST 1.1 Assessed by BICR	PFS was defined as the time from the date of enrollment day to the first documented PD (defined as ≥20% increase in the SOD of target lesions) or death due to any cause, whichever occurred first. Responses are according to RECIST 1.1 as assessed by BICR.	Up to ~36 months
PFS According to iRECIST 1.1 Assessed by BICR	PFS was defined as the time from the date of enrollment day to the first documented PD (defined as ≥20% increase in the SOD of target lesions) or death due to any cause, whichever occurred first. Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.	Up to ~36 months
Overall Survival (OS)	OS was defined as the time from the date of enrollment day to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. For these participants, date of last follow up was last visit date instead of death date.	Up to ~36 months
Number of Participants With ≥1 Adverse Event (AE)	An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment	Up to ~36 months
Number of Participants Discontinuing From Study Treatment Due to AE(s)	An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.	Up to ~36 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Kawazoe A, Yamaguchi K, Yasui H, Negoro Y, Azuma M, Amagai K, Hara H, Baba H, Tsuda M, Hosaka H, Kawakami H, Oshima T, Omuro Y, Machida N, Esaki T, Yoshida K, Nishina T, Komatsu Y, Han SR, Shiratori S, Shitara K. Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study. Eur J Cancer. 2020 Apr;129:97-106. doi: 10.1016/j.ejca.2020.02.002. Epub 2020 Mar 4.
• Yamaguchi K, Minashi K, Sakai D, Nishina T, Omuro Y, Tsuda M, Iwagami S, Kawakami H, Esaki T, Sugimoto N, Oshima T, Kato K, Amagai K, Hosaka H, Komine K, Yasui H, Negoro Y, Ishido K, Tsushima T, Han S, Shiratori S, Takami T, Shitara K. Phase IIb study of pembrolizumab combined with S-1 + oxaliplatin or S-1 + cisplatin as first-line chemotherapy for gastric cancer. Cancer Sci. 2022 Aug;113(8):2814-2827. doi: 10.1111/cas.15462. Epub 2022 Jul 1.

Helpful Links

• Merck Oncology Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2018
• Primary Completion (Actual): May 30, 2021
• Study Completion (Actual): May 30, 2021

Study Registration Dates

• First Submitted: December 19, 2017
• First Submitted That Met QC Criteria: December 19, 2017
• First Posted (Actual): December 26, 2017

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Oxaliplatin; Pembrolizumab
• Other Study ID Numbers: 3475-659; MK-3475-659 (Other Identifier: Merck); KEYNOTE-659 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No