A Study of Pembrolizumab (MK-3475) in Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-059/KEYNOTE-059)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02335411
Collaborator
(none)
318
3
77.6

Study Details

Study Description

Brief Summary

This is a study of pembrolizumab (MK-3475) for advanced gastric or gastroesophageal junction adenocarcinoma; pembrolizumab will be given as monotherapy to participants who have had previous treatment or who are treatment-naïve; pembrolizumab will also be evaluated as combination therapy with cisplatin and 5-Fluorouracil (5-FU) or (Japan only) capecitabine in treatment-naïve participants. The primary study hypothesis is that pembrolizumab will provide a clinically meaningful Overall Response Rate (ORR).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This study will have 3 cohorts. In Cohort 1, participants who have received at least two prior therapies for their advanced disease will receive monotherapy with pembrolizumab. In Cohort 2, participants who have not received any previous therapy for their disease will receive pembrolizumab in combination with cisplatin and 5-FU or (Japan only) capecitabine. In Cohort 3, participants who have not received any previous therapy and who have programmed death ligand 1 (PD-L1)-positive tumors will receive pembrolizumab monotherapy.

Study Design

Study Type:
Interventional
Actual Enrollment :
318 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil in Subjects With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE-059)
Actual Study Start Date :
Feb 3, 2015
Actual Primary Completion Date :
Jul 23, 2021
Actual Study Completion Date :
Jul 23, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1: Pembrolizumab monotherapy, previously treated

Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W)

Biological: pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • Experimental: Cohort 2: Pembrolizumab combination therapy, treatment naive

    Participants receive pembrolizumab 200 mg IV each 3-week cycle (Q3W) + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-FU 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle

    Biological: pembrolizumab
    IV infusion
    Other Names:
  • MK-3475
  • Drug: cisplatin
    IV infusion
    Other Names:
  • PLATINOL®
  • Drug: 5-FU
    IV infusion
    Other Names:
  • ADRUCIL®
  • Drug: capecitabine
    oral tablets
    Other Names:
  • XELODA®
  • Experimental: Cohort 3: Pembrolizumab monotherapy, treatment naive, PD-L1 positive

    Programmed death-ligand 1 (PD-L1) positive participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W)

    Biological: pembrolizumab
    IV infusion
    Other Names:
  • MK-3475
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Experiencing Adverse Events (AEs) [Up to approximately 65 months]

      An AE is defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who experienced at least one AE is presented. Per protocol, the number of participants who experienced at least one AE during first course pembrolizumab treatment is presented.

    2. Number of Participants Discontinuing Study Drug Due to AEs [Up to approximately 52 months]

      An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinued study drug due to an AE is presented. Per protocol, the number of participants who discontinued drug during first course pembrolizumab treatment is presented.

    3. Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3 [Up to approximately 75 months]

      The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of programmed death-ligand 1 [PD-L1] tumor status) in Cohorts 1 and 3 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.

    4. Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3 [Up to approximately 75 months]

      The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of all participants in Cohorts 1 and 3 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

    Secondary Outcome Measures

    1. Objective Response Rate (ORR) For All Participants in Cohort 2 [Up to approximately 75 months]

      The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) in Cohort 2 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.

    2. Objective Response Rate For PD-L1 Positive Participants in Cohort 2 [Up to approximately 75 months]

      The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of participants in Cohort 2 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented.

    3. Duration of Response (DOR) For All Participants [Up to approximately 75 months]

      Duration of Response (DOR) was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.

    4. Duration of Response For PD-L1 Positive Participants [Up to approximately 75 months]

      DOR was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

    5. Progression-Free Survival (PFS) For All Participants [Up to approximately 75 months]

      Progression-Free Survival (PFS) was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.

    6. Progression-Free Survival For PD-L1 Positive Participants [Up to approximately 75 months]

      PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

    7. Overall Survival (OS) For All Participants [Up to approximately 75 months]

      Overall Survival (OS) was defined as the time from randomization 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. The OS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.

    8. Overall Survival For PD-L1 Positive Participants [Up to approximately 75 months]

      OS was defined as the time from randomization 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. The OS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

    9. Disease Control Rate (DCR) For All Participants [Up to approximately 75 months]

      Disease Control Rate (DCR) was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) who had a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented.

    10. Disease Control Rate For PD-L1 Positive Participants [Up to approximately 75 months]

      DCR was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of participants with PD-L1+ tumor status who experienced a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria - Cohort 1:
    • Received and progressed on ≥2 prior chemotherapy regimens for their advanced disease; prior regimen must have included a cisplatin and a fluoropyridine

    • Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu positive, must have previously received treatment with trastuzumab

    Inclusion Criteria - Cohort 2 or 3:
    • HER2/neu negative

    • Has not received prior systemic anti-cancer therapy for their advanced carcinoma (systemic therapy received in the neoadjuvant and adjuvant setting does not count)

    Inclusion Criteria - All Participants:
    • Histologically- or cytologically-confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies

    • Willing to provide tissue for PD-L1 biomarker analysis from newly-obtained and/or archival tissue

    • Measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to first dose of study drug

    • Life expectancy of at least 3 months

    • Female participants of childbearing potential should have a negative pregnancy test and be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU)

    • Male participants should agree to use an adequate method of contraception starting with the first dose through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU)

    • Adequate organ function

    Exclusion Criteria - All Participants:
    • Currently participating and receiving study therapy or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug

    • Active autoimmune disease that has required systemic treatment in past 2 years

    • Immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug

    • Weight loss >10% over 2 months prior to first dose of study drug

    • Clinical evidence of ascites by physical exam

    • Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from AEs due to agents administered more than 4 weeks earlier

    • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from AEs due to a previously administered agent

    • Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

    • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

    • Known history of, or any evidence of active, non-infectious pneumonitis

    • Active infection requiring systemic therapy

    • Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

    • 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 drug (180 days for participants receiving cisplatin + 5FU)

    • Prior therapy with an anti-programmed death-1 (PD-1), anti-PD-L1, or anti-PD-L2 agent

    • Human immunodeficiency virus (HIV)

    • Hepatitis B or C

    • Received live vaccine within 30 days of planned start of study drug

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02335411
    Other Study ID Numbers:
    • 3475-059
    • MK-3475-059
    • KEYNOTE-059
    • 2014-003574-16
    First Posted:
    Jan 9, 2015
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Merck Sharp & Dohme LLC
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Male and female participants of at least 18 years of age with recurrent or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma were enrolled in this study.
    Pre-assignment Detail 318 participants were originally allocated to the study. No study information was collected from 3 participants, who were excluded from all analyses, including disposition. Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures respectively.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Period Title: Overall Study
    STARTED 259 25 31
    Second Course Pembrolizumab 3 1 2
    COMPLETED 0 0 0
    NOT COMPLETED 259 25 31

    Baseline Characteristics

    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive Total
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Total of all reporting groups
    Overall Participants 259 25 31 315
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    61.0
    (11.4)
    58.8
    (16.6)
    60.3
    (11.2)
    60.7
    (11.9)
    Sex: Female, Male (Count of Participants)
    Female
    61
    23.6%
    9
    36%
    12
    38.7%
    82
    26%
    Male
    198
    76.4%
    16
    64%
    19
    61.3%
    233
    74%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    17
    6.6%
    1
    4%
    3
    9.7%
    21
    6.7%
    Not Hispanic or Latino
    228
    88%
    23
    92%
    28
    90.3%
    279
    88.6%
    Unknown or Not Reported
    14
    5.4%
    1
    4%
    0
    0%
    15
    4.8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    41
    15.8%
    17
    68%
    15
    48.4%
    73
    23.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    5
    1.9%
    0
    0%
    0
    0%
    5
    1.6%
    White
    200
    77.2%
    8
    32%
    16
    51.6%
    224
    71.1%
    More than one race
    2
    0.8%
    0
    0%
    0
    0%
    2
    0.6%
    Unknown or Not Reported
    11
    4.2%
    0
    0%
    0
    0%
    11
    3.5%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Experiencing Adverse Events (AEs)
    Description An AE is defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who experienced at least one AE is presented. Per protocol, the number of participants who experienced at least one AE during first course pembrolizumab treatment is presented.
    Time Frame Up to approximately 65 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 25 31
    Count of Participants [Participants]
    248
    95.8%
    25
    100%
    31
    100%
    2. Primary Outcome
    Title Number of Participants Discontinuing Study Drug Due to AEs
    Description An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinued study drug due to an AE is presented. Per protocol, the number of participants who discontinued drug during first course pembrolizumab treatment is presented.
    Time Frame Up to approximately 52 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 25 31
    Count of Participants [Participants]
    18
    6.9%
    4
    16%
    0
    0%
    3. Primary Outcome
    Title Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3
    Description The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of programmed death-ligand 1 [PD-L1] tumor status) in Cohorts 1 and 3 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants in Cohorts 1 and 3 who received ≥1 dose of study drug. Per protocol, Cohort 2 was not included in this outcome measure.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 0 31
    Number (95% Confidence Interval) [Percentage of Participants]
    11.6
    4.5%
    22.6
    90.4%
    4. Primary Outcome
    Title Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3
    Description The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of all participants in Cohorts 1 and 3 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants in Cohorts 1 and 3 with a positive PD-L1 tumor status who received ≥1 dose of study drug. Per protocol, Cohort 2 was not included in this outcome measure.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 148 0 31
    Number (95% Confidence Interval) [Percentage of Participants]
    15.5
    6%
    22.6
    90.4%
    5. Secondary Outcome
    Title Objective Response Rate (ORR) For All Participants in Cohort 2
    Description The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) in Cohort 2 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants in Cohort 2 who received ≥1 dose of study drug. Per protocol, Cohorts 1 and 3 were not included in this outcome measure.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 0 25 0
    Number (95% Confidence Interval) [Percentage of Participants]
    60.0
    23.2%
    6. Secondary Outcome
    Title Objective Response Rate For PD-L1 Positive Participants in Cohort 2
    Description The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of participants in Cohort 2 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants in Cohort 2 with a positive PD-L1 tumor status who received ≥1 dose of study drug. Per protocol, Cohorts 1 and 3 were not included in this outcome measure.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 0 15 0
    Number (95% Confidence Interval) [Percentage of Participants]
    73.3
    28.3%
    7. Secondary Outcome
    Title Duration of Response (DOR) For All Participants
    Description Duration of Response (DOR) was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug and demonstrated a confirmed response (CR or PR).
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 30 15 7
    Median (Full Range) [Months]
    16.1
    4.6
    38.0
    8. Secondary Outcome
    Title Duration of Response For PD-L1 Positive Participants
    Description DOR was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug and demonstrated a confirmed response (CR or PR).
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 23 11 7
    Median (Full Range) [Months]
    NA
    4.6
    38.0
    9. Secondary Outcome
    Title Progression-Free Survival (PFS) For All Participants
    Description Progression-Free Survival (PFS) was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 25 31
    Median (95% Confidence Interval) [Months]
    2.0
    6.6
    2.9
    10. Secondary Outcome
    Title Progression-Free Survival For PD-L1 Positive Participants
    Description PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 148 15 31
    Median (95% Confidence Interval) [Months]
    2.1
    6.5
    2.9
    11. Secondary Outcome
    Title Overall Survival (OS) For All Participants
    Description Overall Survival (OS) was defined as the time from randomization 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. The OS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 25 31
    Median (95% Confidence Interval) [Months]
    5.5
    13.8
    20.7
    12. Secondary Outcome
    Title Overall Survival For PD-L1 Positive Participants
    Description OS was defined as the time from randomization 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. The OS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 148 15 31
    Median (95% Confidence Interval) [Months]
    5.8
    11.1
    20.7
    13. Secondary Outcome
    Title Disease Control Rate (DCR) For All Participants
    Description Disease Control Rate (DCR) was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) who had a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 259 25 31
    Number (95% Confidence Interval) [Percentage of Participants]
    27.0
    10.4%
    80.0
    320%
    32.3
    104.2%
    14. Secondary Outcome
    Title Disease Control Rate For PD-L1 Positive Participants
    Description DCR was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of participants with PD-L1+ tumor status who experienced a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
    Time Frame Up to approximately 75 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.
    Arm/Group Title Cohort 1: Pembrolizumab Monotherapy, Previously Treated Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
    Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year. Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
    Measure Participants 148 15 31
    Number (95% Confidence Interval) [Percentage of Participants]
    33.1
    12.8%
    80.0
    320%
    32.3
    104.2%

    Adverse Events

    Time Frame Up to approximately 75 months
    Adverse Event Reporting Description The population analyzed for all-cause mortality consisted of all allocated participants. The population for AEs consisted of all allocated participants who received ≥1 dose of study drug. Per protocol disease progression of cancer was not considered an AE unless related to study drug. Therefore the following AE preferred terms not related to the drug were excluded: Neoplasm progression, Malignant neoplasm progression and Disease progression.
    Arm/Group Title Cohort 1 First Course Cohort 2 First Course Cohort 3 First Course Cohort 1 Second Course Cohort 2 Second Course Cohort 3 Second Course
    Arm/Group Description Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-FU 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, BID on Days 1-14 of each 3-week cycle. PD-L1 positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months Eligible participants allocated to the pembrolizumab first course in Cohort 1 who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year. Eligible participants allocated to the pembrolizumab first course in Cohort 2 who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year. Eligible participants allocated to the pembrolizumab first course in Cohort 3 who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year.
    All Cause Mortality
    Cohort 1 First Course Cohort 2 First Course Cohort 3 First Course Cohort 1 Second Course Cohort 2 Second Course Cohort 3 Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 244/259 (94.2%) 21/25 (84%) 26/31 (83.9%) 1/3 (33.3%) 1/1 (100%) 1/2 (50%)
    Serious Adverse Events
    Cohort 1 First Course Cohort 2 First Course Cohort 3 First Course Cohort 1 Second Course Cohort 2 Second Course Cohort 3 Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 119/259 (45.9%) 11/25 (44%) 15/31 (48.4%) 0/3 (0%) 0/1 (0%) 0/2 (0%)
    Blood and lymphatic system disorders
    Abdominal lymphadenopathy 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Anaemia 6/259 (2.3%) 6 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cardiac disorders
    Atrial fibrillation 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cardiac arrest 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cardiac tamponade 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Myocardial infarction 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pericardial effusion 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Supraventricular tachycardia 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Endocrine disorders
    Hypothyroidism 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Thyroiditis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Eye disorders
    Diffuse uveal melanocytic proliferation 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 4/259 (1.5%) 4 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Abdominal pain upper 3/259 (1.2%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Ascites 2/259 (0.8%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Colitis 2/259 (0.8%) 2 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Constipation 3/259 (1.2%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Diarrhoea 3/259 (1.2%) 3 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Diverticulum intestinal haemorrhagic 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dysphagia 7/259 (2.7%) 7 1/25 (4%) 1 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Enterocolitis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastric haemorrhage 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastric perforation 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastric stenosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastrointestinal haemorrhage 3/259 (1.2%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Haematemesis 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Ileus 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Intestinal obstruction 6/259 (2.3%) 6 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Jejunal perforation 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Large intestinal obstruction 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Melaena 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Nausea 5/259 (1.9%) 7 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Obstruction gastric 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oesophageal intramural haematoma 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oesophageal perforation 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oesophageal stenosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oesophageal ulcer 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Small intestinal obstruction 2/259 (0.8%) 2 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Stomatitis 0/259 (0%) 0 4/25 (16%) 4 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Upper gastrointestinal haemorrhage 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vomiting 5/259 (1.9%) 6 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    General disorders
    Asthenia 4/259 (1.5%) 4 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Chest pain 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Death 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Fatigue 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastrointestinal complication associated with device 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Influenza like illness 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Multiple organ dysfunction syndrome 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Non-cardiac chest pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pyrexia 3/259 (1.2%) 3 1/25 (4%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Systemic inflammatory response syndrome 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatobiliary disorders
    Bile duct stenosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Biliary obstruction 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cholangitis 1/259 (0.4%) 1 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cholecystitis acute 1/259 (0.4%) 1 1/25 (4%) 1 1/31 (3.2%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatic failure 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatic function abnormal 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatic haematoma 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatic pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hepatitis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Jaundice 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Portal vein thrombosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Infections and infestations
    Abdominal abscess 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Bacteraemia 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Clostridium difficile infection 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Disseminated varicella zoster virus infection 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Diverticulitis intestinal haemorrhagic 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Encephalitis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Liver abscess 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Osteomyelitis 1/259 (0.4%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pharyngitis 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumocystis jirovecii pneumonia 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumonia 4/259 (1.5%) 6 0/25 (0%) 0 2/31 (6.5%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pyelonephritis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Sepsis 5/259 (1.9%) 5 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Septic shock 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Staphylococcal bacteraemia 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Subdiaphragmatic abscess 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Urinary tract infection 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Wound infection 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Post procedural haemorrhage 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Rib fracture 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Thoracic vertebral fracture 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vascular pseudoaneurysm 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Aspartate aminotransferase increased 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Blood bilirubin increased 1/259 (0.4%) 1 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Blood creatine phosphokinase increased 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Blood creatinine increased 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Transaminases increased 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Urine output decreased 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 1/259 (0.4%) 1 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dehydration 4/259 (1.5%) 4 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Failure to thrive 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypercalcaemia 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hyperglycaemia 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hyponatraemia 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Back pain 5/259 (1.9%) 5 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Musculoskeletal chest pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Musculoskeletal pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Myositis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Neck pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pain in extremity 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Polymyalgia rheumatica 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Metastases to adrenals 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oesophageal squamous cell carcinoma 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Renal cancer 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Squamous cell carcinoma of skin 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Tumour pain 3/259 (1.2%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Nervous system disorders
    Altered state of consciousness 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cauda equina syndrome 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Cerebrovascular accident 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dizziness 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dysarthria 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Seizure 1/259 (0.4%) 1 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Syncope 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Transient ischaemic attack 1/259 (0.4%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Unresponsive to stimuli 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vertebral artery occlusion 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Psychiatric disorders
    Anxiety 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Confusional state 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Delirium 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Depression 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Drug dependence 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 6/259 (2.3%) 6 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Chronic kidney disease 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hydronephrosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Nephrotic syndrome 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 3/259 (1.2%) 3 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypoxia 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pleural effusion 9/259 (3.5%) 9 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumonia aspiration 2/259 (0.8%) 2 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumonitis 2/259 (0.8%) 2 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pulmonary embolism 6/259 (2.3%) 6 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Respiratory failure 2/259 (0.8%) 2 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Skin and subcutaneous tissue disorders
    Lichen planus 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/259 (0%) 0 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Rash maculo-papular 0/259 (0%) 0 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Embolism 1/259 (0.4%) 1 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Haematoma 0/259 (0%) 0 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Internal haemorrhage 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vena cava thrombosis 1/259 (0.4%) 1 0/25 (0%) 0 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Other (Not Including Serious) Adverse Events
    Cohort 1 First Course Cohort 2 First Course Cohort 3 First Course Cohort 1 Second Course Cohort 2 Second Course Cohort 3 Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 237/259 (91.5%) 25/25 (100%) 31/31 (100%) 0/3 (0%) 0/1 (0%) 0/2 (0%)
    Blood and lymphatic system disorders
    Anaemia 58/259 (22.4%) 69 11/25 (44%) 13 7/31 (22.6%) 9 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Leukopenia 4/259 (1.5%) 7 2/25 (8%) 3 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Neutropenia 3/259 (1.2%) 3 9/25 (36%) 12 1/31 (3.2%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Thrombocytopenia 8/259 (3.1%) 10 3/25 (12%) 5 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Ear and labyrinth disorders
    Tinnitus 0/259 (0%) 0 4/25 (16%) 4 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Endocrine disorders
    Hyperthyroidism 10/259 (3.9%) 10 4/25 (16%) 4 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypothyroidism 24/259 (9.3%) 24 2/25 (8%) 2 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 2/259 (0.8%) 2 2/25 (8%) 2 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Abdominal distension 15/259 (5.8%) 15 2/25 (8%) 2 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Abdominal pain 49/259 (18.9%) 56 3/25 (12%) 3 8/31 (25.8%) 13 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Abdominal pain upper 19/259 (7.3%) 25 4/25 (16%) 8 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Ascites 16/259 (6.2%) 18 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Constipation 52/259 (20.1%) 57 14/25 (56%) 22 7/31 (22.6%) 7 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Diarrhoea 46/259 (17.8%) 55 14/25 (56%) 18 8/31 (25.8%) 13 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dry mouth 8/259 (3.1%) 8 2/25 (8%) 4 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dyspepsia 9/259 (3.5%) 9 2/25 (8%) 3 3/31 (9.7%) 4 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dysphagia 31/259 (12%) 36 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gastrooesophageal reflux disease 10/259 (3.9%) 12 2/25 (8%) 4 2/31 (6.5%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Nausea 65/259 (25.1%) 74 15/25 (60%) 22 8/31 (25.8%) 10 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Stomatitis 10/259 (3.9%) 10 17/25 (68%) 29 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vomiting 36/259 (13.9%) 44 10/25 (40%) 23 6/31 (19.4%) 12 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    General disorders
    Asthenia 24/259 (9.3%) 26 4/25 (16%) 7 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Chest discomfort 2/259 (0.8%) 2 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Fatigue 93/259 (35.9%) 105 10/25 (40%) 13 10/31 (32.3%) 10 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Generalised oedema 0/259 (0%) 0 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Influenza like illness 4/259 (1.5%) 5 0/25 (0%) 0 4/31 (12.9%) 5 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Malaise 7/259 (2.7%) 7 5/25 (20%) 14 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Mucosal inflammation 1/259 (0.4%) 1 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oedema 9/259 (3.5%) 9 4/25 (16%) 10 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oedema peripheral 43/259 (16.6%) 57 1/25 (4%) 1 4/31 (12.9%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pyrexia 25/259 (9.7%) 35 6/25 (24%) 9 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Infections and infestations
    Nasopharyngitis 7/259 (2.7%) 8 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumonia 8/259 (3.1%) 10 2/25 (8%) 3 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Investigations
    Alanine aminotransferase increased 14/259 (5.4%) 19 2/25 (8%) 3 2/31 (6.5%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Aspartate aminotransferase increased 30/259 (11.6%) 34 2/25 (8%) 2 4/31 (12.9%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Blood alkaline phosphatase increased 31/259 (12%) 32 1/25 (4%) 1 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Blood creatinine increased 13/259 (5%) 15 5/25 (20%) 6 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Gamma-glutamyltransferase increased 7/259 (2.7%) 9 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Haemoglobin decreased 4/259 (1.5%) 4 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Lymphocyte count decreased 6/259 (2.3%) 8 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Neutrophil count decreased 2/259 (0.8%) 3 13/25 (52%) 30 1/31 (3.2%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Platelet count decreased 3/259 (1.2%) 4 5/25 (20%) 7 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Weight decreased 38/259 (14.7%) 41 5/25 (20%) 6 4/31 (12.9%) 4 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Weight increased 2/259 (0.8%) 2 3/25 (12%) 13 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    White blood cell count decreased 2/259 (0.8%) 2 4/25 (16%) 9 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 73/259 (28.2%) 81 13/25 (52%) 22 11/31 (35.5%) 14 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dehydration 15/259 (5.8%) 20 2/25 (8%) 2 2/31 (6.5%) 4 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Diabetes mellitus 0/259 (0%) 0 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hyperglycaemia 23/259 (8.9%) 29 3/25 (12%) 6 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypoalbuminaemia 24/259 (9.3%) 24 1/25 (4%) 1 4/31 (12.9%) 4 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypokalaemia 12/259 (4.6%) 13 3/25 (12%) 3 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypomagnesaemia 2/259 (0.8%) 2 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hyponatraemia 23/259 (8.9%) 26 1/25 (4%) 2 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypophosphataemia 10/259 (3.9%) 14 2/25 (8%) 4 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 36/259 (13.9%) 58 3/25 (12%) 3 5/31 (16.1%) 8 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Back pain 34/259 (13.1%) 38 2/25 (8%) 2 6/31 (19.4%) 7 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Flank pain 5/259 (1.9%) 5 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Groin pain 3/259 (1.2%) 3 0/25 (0%) 0 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Muscular weakness 3/259 (1.2%) 3 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Myalgia 8/259 (3.1%) 10 2/25 (8%) 2 5/31 (16.1%) 7 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pain in extremity 9/259 (3.5%) 12 0/25 (0%) 0 5/31 (16.1%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Nervous system disorders
    Dizziness 17/259 (6.6%) 17 4/25 (16%) 5 4/31 (12.9%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dysgeusia 6/259 (2.3%) 6 6/25 (24%) 9 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Headache 12/259 (4.6%) 13 5/25 (20%) 5 3/31 (9.7%) 6 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Neuropathy peripheral 3/259 (1.2%) 3 3/25 (12%) 3 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Peripheral sensory neuropathy 5/259 (1.9%) 5 6/25 (24%) 7 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Syncope 2/259 (0.8%) 3 2/25 (8%) 3 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Psychiatric disorders
    Anxiety 15/259 (5.8%) 18 0/25 (0%) 0 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Insomnia 17/259 (6.6%) 20 9/25 (36%) 9 2/31 (6.5%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 44/259 (17%) 50 2/25 (8%) 2 6/31 (19.4%) 8 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dyspnoea 40/259 (15.4%) 43 1/25 (4%) 2 5/31 (16.1%) 7 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Epistaxis 3/259 (1.2%) 3 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hiccups 4/259 (1.5%) 4 8/25 (32%) 16 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Oropharyngeal pain 8/259 (3.1%) 8 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pleural effusion 11/259 (4.2%) 14 2/25 (8%) 2 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pneumonitis 2/259 (0.8%) 2 1/25 (4%) 1 3/31 (9.7%) 4 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 3/259 (1.2%) 3 4/25 (16%) 4 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Dry skin 17/259 (6.6%) 18 2/25 (8%) 2 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 1/259 (0.4%) 1 3/25 (12%) 3 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Pruritus 33/259 (12.7%) 39 4/25 (16%) 7 8/31 (25.8%) 10 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Rash 31/259 (12%) 33 2/25 (8%) 2 3/31 (9.7%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Rash maculo-papular 5/259 (1.9%) 5 1/25 (4%) 1 2/31 (6.5%) 3 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Skin hyperpigmentation 1/259 (0.4%) 1 2/25 (8%) 2 1/31 (3.2%) 1 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Skin lesion 3/259 (1.2%) 3 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Urticaria 1/259 (0.4%) 1 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vascular disorders
    Hypertension 14/259 (5.4%) 20 1/25 (4%) 1 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Hypotension 10/259 (3.9%) 12 0/25 (0%) 0 2/31 (6.5%) 2 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0
    Vasculitis 0/259 (0%) 0 2/25 (8%) 2 0/31 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/2 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme LLC
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02335411
    Other Study ID Numbers:
    • 3475-059
    • MK-3475-059
    • KEYNOTE-059
    • 2014-003574-16
    First Posted:
    Jan 9, 2015
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Jul 1, 2022