Study of Pembrolizumab (MK-3475) as First-Line Monotherapy and Combination Therapy for Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-062/KEYNOTE-062)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02494583
• Collaborator: (none)
• Enrollment: 763
• Arms: 3
• Actual Duration (Months): 82.2

Study Details

Study Description

Brief Summary

This is a study of pembrolizumab (MK-3475) as first-line treatment for participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Participants whose tumors express programmed death-ligand 1 (PD-L1) will be randomly assigned to one of the three treatment arms of the study: pembrolizumab as monotherapy [pembro mono], pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [pembro combo], or placebo plus SOC chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [SOC].

The primary study hypotheses are that pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of Progression-free Survival (PFS) and Overall Survival (OS) in participants with PD-L1 Combined Positive Score (CPS) ≥1, pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥10, pembrolizumab monotherapy is non-inferior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1, and pembrolizumab monotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1 and in participants with PD-L1 CPS ≥10.

Condition or Disease	Intervention/Treatment	Phase
Gastric Adenocarcinoma	Biological: Pembrolizumab; Drug: Cisplatin; Drug: 5-FU; Drug: Capecitabine; Drug: Placebo	Phase 3

Detailed Description

As specified by the protocol, primary and secondary efficacy analyses will be evaluated in gastric cancer participants with PD-L1 CPS ≥1 (all participants) and PD-L1 CPS ≥10 (OS) by comparing the pembro mono arm or pembro combo arm separately to the SOC arm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 763 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: This study is partially blinded. The participant, study site personnel, and the sponsor will be blinded in the pembrolizumab plus SOC chemotherapy (pembro combo) arm and the placebo plus SOC chemotherapy (SOC) arm, but not in the pembro monotherapy (mono arm) since only one type of study medication will be administered.
• Primary Purpose: Treatment
• Official Title: A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil Versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects With Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
• Actual Study Start Date: Jul 31, 2015
• Actual Primary Completion Date: Mar 26, 2019
• Actual Study Completion Date: Jun 6, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Monotherapy (Pembro Mono) Participants receive pembrolizumab 200 mg, intravenously (IV) on Day 1 of each 3-week cycle (Q3W)	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each week in 3-week cycles for up to 35 cycles (approximately 2 years).; Other Names: MK-3475 KEYTRUDA®
Experimental: Pembrolizumab + SOC Chemotherapy (Pembro Combo) Participants receive pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each week in 3-week cycles for up to 35 cycles (approximately 2 years).; Other Names: MK-3475 KEYTRUDA® ; Drug: Cisplatin; Cisplatin 80 mg/m^2 IV on Day 1 of each week in 3-week cycles (6 cycle maximum per local country guidelines).; Drug: 5-FU; 5-FU 800 mg/m^2/day IV continuous from Day 1-5 of each 3-week cycle.; Drug: Capecitabine; Capecitabine 1000 mg/m^2 twice daily by oral tablet on Day 1-14 of each 3-week cycle.
Placebo Comparator: Placebo + SOC Chemotherapy (SOC) Participants receive placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.	Drug: Cisplatin; Cisplatin 80 mg/m^2 IV on Day 1 of each week in 3-week cycles (6 cycle maximum per local country guidelines).; Drug: 5-FU; 5-FU 800 mg/m^2/day IV continuous from Day 1-5 of each 3-week cycle.; Drug: Capecitabine; Capecitabine 1000 mg/m^2 twice daily by oral tablet on Day 1-14 of each 3-week cycle.; Drug: Placebo; Normal saline IV on Day 1 of each week in 3-week cycles for up to 35 cycles (approximately 2 years).

Outcome Measures

Primary Outcome Measures

1. Pembro Combo vs SOC: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 36 months (through Interim Analysis cut-off date of 26-Sep-2018)]

   PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population. PFS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.

2. Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   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. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.

3. Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10 [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   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. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro mono arm and SOC arm and is presented later in the record.

4. Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   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. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.

5. Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10 [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   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. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro combo arm and SOC arm and is presented earlier in the record.

Secondary Outcome Measures

1. Pembro Combo vs SOC: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.

2. Pembro Combo vs SOC: Duration of Response (DOR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants) and had CR or PR. Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro mono arm and SOC arm and is presented later in the record.

3. Pembro Mono vs SOC: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.

4. Pembro Mono vs SOC: DOR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants) and had CR or PR. Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro combo arm and SOC arm and is presented earlier in the record.

5. Pembro Mono vs SOC: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants) [Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)]

   PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.

6. Pembro Mono vs SOC: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score [Baseline, Week 18]

   The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro mono arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and SOC arm and is presented later in the record.

7. Pembro Combo vs SOC: Change From Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score [Baseline, Week 18]

   The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro mono arm and SOC arm and is presented earlier in the record.

8. Pembro Mono vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score [Baseline, Week 18]

   EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared between the pembro mono arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro combo arm and SOC arm and is presented later in the record.

9. Pembro Combo vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score [Baseline, Week 18]

   EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared between the pembro combo arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro mono arm and SOC arm and is presented earlier in the record.

10. Number of Participants Experiencing an Adverse Event (AE) [Up to approximately 31.5 months]

    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received.

11. Number of Participants Discontinuing Study Treatment Due to an AE [Up to approximately 28.5 months]

    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an adverse event. The number of participants who discontinued study treatment due to an AE was reported for each arm according to the treatment received.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to first dose of study medication

• Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma

• Human epidermal growth factor receptor 2- (HER2/neu-) negative and programmed cell death ligand 1 (PD-L1)-positive

• Has measurable disease

• Female participants of childbearing potential must be willing to use adequate contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication

• Male participants of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study medication

• Adequate organ function

Exclusion Criteria:

• Squamous cell or undifferentiated gastric cancer

• Previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participant may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization

• Major surgery, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment.

• Radiotherapy within 14 days of randomization

• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, 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

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

• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication

• History of non-infectious pneumonitis that required steroids or current pneumonitis

• Active infection requiring systemic therapy

• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication

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

• Known history of human immunodeficiency virus (HIV)

• Known active Hepatitis B or C

• Currently participating in and receiving study therapy or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study medication

• Received a live vaccine within 30 days prior to the first dose of study medication

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)

• Study Protocol and Statistical Analysis Plan - Jan 23, 2019

More Information

Additional Information:

• Merck Oncology Clinical Trial Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02494583
• Other Study ID Numbers: 3475-062; 163187; MK-3475-062; KEYNOTE-062; 2015-000972-88
• First Posted: Jul 10, 2015
• Last Update Posted: Aug 19, 2022
• Last Verified: Aug 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: Gastric carcinoma; Gastric cancer; Gastroesophageal junction cancer; Gastroesophageal junction carcinoma; Programmed Cell Death-1 (PD1, PD-1),; Programmed Death-Ligand 1 (PDL1, PD-L1); Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
• Additional relevant MeSH terms: Adenocarcinoma; Pembrolizumab; Capecitabine

Study Results

Participant Flow

Recruitment Details	Participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who were programmed death-ligand 1 (PD-L1)-positive (Combined Positive Score [CPS]≥1) and human epidermal growth factor receptor 2 (HER2/neu)-negative were recruited to the study.
Pre-assignment Detail	Of 1,787 screened, 763 were randomized 1:1:1 to the pembrolizumab monotherapy (pembro mono) arm, pembrolizumab plus standard of care (SOC) chemotherapy (pembro combo) arm, or placebo plus SOC chemotherapy (SOC) arm.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W)	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-fluorouracil (5-FU) 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Period Title: Overall Study
STARTED	256	257	250
Treated	254	250	244
COMPLETED	0	0	0
NOT COMPLETED	256	257	250

Baseline Characteristics

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)	Total
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Total of all reporting groups
Overall Participants	256	257	250	763
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.9 (11.6)	60.9 (11.6)	60.7 (12.7)	60.5 (12.0)
Sex: Female, Male (Count of Participants)
Female	76 29.7%	62 24.1%	71 28.4%	209 27.4%
Male	180 70.3%	195 75.9%	179 71.6%	554 72.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	45 17.6%	54 21%	46 18.4%	145 19%
Not Hispanic or Latino	206 80.5%	196 76.3%	197 78.8%	599 78.5%
Unknown or Not Reported	5 2%	7 2.7%	7 2.8%	19 2.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	9 3.5%	7 2.7%	13 5.2%	29 3.8%
Asian	69 27%	71 27.6%	67 26.8%	207 27.1%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.4%	2 0.3%
Black or African American	4 1.6%	4 1.6%	5 2%	13 1.7%
White	164 64.1%	167 65%	154 61.6%	485 63.6%
More than one race	9 3.5%	6 2.3%	7 2.8%	22 2.9%
Unknown or Not Reported	0 0%	2 0.8%	3 1.2%	5 0.7%
Region of Enrollment (Number) [Number]
Europe/North America/Australia	148 57.8%	148 57.6%	147 58.8%	443 58.1%
Asia	62 24.2%	64 24.9%	61 24.4%	187 24.5%
Rest of the World	46 18%	45 17.5%	42 16.8%	133 17.4%
Disease Status (Count of Participants)
Locally advanced	10 3.9%	12 4.7%	13 5.2%	35 4.6%
Metastatic	245 95.7%	243 94.6%	235 94%	723 94.8%
Missing	1 0.4%	2 0.8%	2 0.8%	5 0.7%
Fluoropyrimidine Treatment (Count of Participants)
5-FU	97 37.9%	98 38.1%	95 38%	290 38%
Capecitabine	159 62.1%	159 61.9%	155 62%	473 62%

Outcome Measures

1. Primary Outcome

Title	Pembro Combo vs SOC: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants)
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population. PFS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.
Time Frame	Up to approximately 36 months (through Interim Analysis cut-off date of 26-Sep-2018)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	257	250
Median (95% Confidence Interval) [Months]	6.9	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	PFS in CPS ≥1 participants of the pembro combo arm was compared to PFS in CPS ≥1 participants of the SOC arm to address the first primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and fluoropyrimidine treatment.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03918
	Comments	One-sided p-value based on log-rank test with stratification.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

2. Primary Outcome

Title	Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All 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. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	257	250
Median (95% Confidence Interval) [Months]	12.5	11.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	OS in CPS ≥1 participants of the pembro combo arm was compared to OS in CPS ≥1 participants of the SOC arm to address the second primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.04611
	Comments	One-sided p-value based on log-rank test with stratification.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

3. Primary Outcome

Title	Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10
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. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro mono arm and SOC arm and is presented later in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥10 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	99	90
Median (95% Confidence Interval) [Months]	12.3	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	OS in CPS ≥10 participants of the pembro combo arm was compared to OS in CPS ≥10 participants of the SOC arm to address the third primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15804
	Comments	One-sided p-value based on log-rank test with stratification.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

4. Primary Outcome

Title	Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All 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. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	256	0	250
Median (95% Confidence Interval) [Months]	10.6	11.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the SOC arm to address the fourth primary hypothesis (non-inferiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Non-Inferiority
	Comments	Pre-specified non-inferiority margin: if the upper bound of the confidence interval (based on the alpha level allocated to the analysis) for the hazard ratio ([HR], pembro mono arm vs SOC) is < 1.2, the pembro mono arm could be considered as non-inferior to the SOC arm in terms of OS.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 99.2%; 0.69 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the SOC arm to address the fifth primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.16205
	Comments	One-sided p-value based on log-rank test with stratification.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

5. Primary Outcome

Title	Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10
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. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥10 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	92	0	90
Median (95% Confidence Interval) [Months]	17.4	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	OS in CPS ≥10 participants of the pembro mono arm was compared to OS in CPS ≥10 participants of the SOC arm to address the sixth primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01491
	Comments	One-sided p-value based on log-rank test with stratification.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

6. Secondary Outcome

Title	Pembro Combo vs SOC: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
Description	ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	257	250
Number (95% Confidence Interval) [Percentage of Participants]	48.6 19%	37.2 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	ORR in CPS ≥1 participants of the pembro combo arm was compared to ORR in CPS ≥1 participants of the SOC arm based on Miettinen & Nurminen method stratified by geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00447
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	11.5
	Confidence Interval	(2-Sided) 95%; 2.9 to 20.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

7. Secondary Outcome

Title	Pembro Combo vs SOC: Duration of Response (DOR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants) and had CR or PR. Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro mono arm and SOC arm and is presented later in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm and who demonstrated a confirmed CR or PR were analyzed. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	125	93
Median (Full Range) [Months]	NA	NA

8. Secondary Outcome

Title	Pembro Mono vs SOC: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
Description	ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	256	0	250
Number (95% Confidence Interval) [Percentage of Participants]	14.8 5.8%	37.2 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	ORR in CPS ≥1 participants of the pembro mono arm was compared to ORR in CPS ≥1 participants of the SOC arm based on Miettinen & Nurminen method stratified by geographic region, disease status, and Fluoropyrimidine treatment.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.99999
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	-22.3
	Confidence Interval	(2-Sided) 95%; -29.6 to -14.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

9. Secondary Outcome

Title	Pembro Mono vs SOC: DOR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants) and had CR or PR. Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro combo arm and SOC arm and is presented earlier in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm and who demonstrated a confirmed CR or PR were analyzed. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	38	0	93
Median (Full Range) [Months]	NA	NA

10. Secondary Outcome

Title	Pembro Mono vs SOC: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
Description	PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)

Outcome Measure Data

Analysis Population Description

All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	256	0	250
Median (95% Confidence Interval) [Months]	2.0	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	PFS in CPS ≥1 participants of the pembro mono arm was compared to PFS in CPS ≥1 participants of the SOC arm based on a Cox regression model with Efron's method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and fluoropyrimidine treatment.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00000
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95%; 1.36 to 1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

11. Secondary Outcome

Title	Pembro Mono vs SOC: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Description	The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro mono arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and SOC arm and is presented later in the record.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

Participants in the pembro mono arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 18. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	251	0	243
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-1.91	-1.75

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro mono arm and the SOC arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.948
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -5.01 to 4.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified analyses could be based on collapsing strata with insufficient number of participants or events; strata were pooled in some cases based on clinical judgement and actual counts.

12. Secondary Outcome

Title	Pembro Combo vs SOC: Change From Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Description	The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro mono arm and SOC arm and is presented earlier in the record.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

Participants in the pembro combo arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 18. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	245	243
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-0.09	-2.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.368
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.98
	Confidence Interval	(2-Sided) 95%; -2.34 to 6.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

13. Secondary Outcome

Title	Pembro Mono vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score
Description	EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared between the pembro mono arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro combo arm and SOC arm and is presented later in the record.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

Participants in the pembro mono arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-STO22 assessments available at baseline or post-baseline up to Week 18. Per protocol, the pembro combo arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	251	0	243
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-1.14	-3.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Monotherapy (Pembro Mono), Placebo + SOC Chemotherapy (SOC)
	Comments	Change from baseline to Week 18 in EORTC-QLQ-STO22 Pain symptom subscale score was compared between all participants of the pembro mono arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	2.35
	Confidence Interval	(2-Sided) 95%; -2.18 to 6.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

14. Secondary Outcome

Title	Pembro Combo vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score
Description	EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared between the pembro combo arm and the SOC arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro mono arm and SOC arm and is presented earlier in the record.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

Participants in the pembro combo arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-STO22 assessments available at baseline or post-baseline up to Week 18. Per protocol, the pembro mono arm was compared to the SOC arm separately and not included in this analysis.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	0	245	243
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-10.12	-3.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + SOC Chemotherapy (Pembro Combo), Placebo + SOC Chemotherapy (SOC)
	Comments	Change from baseline to Week 18 in EORTC-QLQ-STO22 Pain symptom subscale score was compared between all participants of the pembro combo arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-6.56
	Confidence Interval	(2-Sided) 95%; -10.55 to -2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Since stratified analyses could be based on collapsing strata with insufficient number of participants or events, strata were pooled in some cases based on clinical judgement and actual counts.

15. Secondary Outcome

Title	Number of Participants Experiencing an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received.
Time Frame	Up to approximately 31.5 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of trial treatment were analyzed.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	254	250	244
Count of Participants [Participants]	242 94.5%	244 94.9%	240 96%

16. Secondary Outcome

Title	Number of Participants Discontinuing Study Treatment Due to an AE
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an adverse event. The number of participants who discontinued study treatment due to an AE was reported for each arm according to the treatment received.
Time Frame	Up to approximately 28.5 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of trial treatment were analyzed.

Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + SOC Chemotherapy (Pembro Combo)	Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.	Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.	Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
Measure Participants	254	250	244
Count of Participants [Participants]	27 10.5%	85 33.1%	58 23.2%

Adverse Events

Time Frame	Up to approximately 42 months (through Final Analysis cut-off date of 26-Mar-2019)
Adverse Event Reporting Description	All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all randomized participants who received at least 1 dose of study treatment. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Arm/Group Title	Pembrolizumab Monotherapy (Pembro Mono)		Pembrolizumab + SOC Chemotherapy (Pembro Combo)		Placebo + SOC Chemotherapy (SOC)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W.		Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.		Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
All Cause Mortality
	Pembrolizumab Monotherapy (Pembro Mono)		Pembrolizumab + SOC Chemotherapy (Pembro Combo)		Placebo + SOC Chemotherapy (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	201/256 (78.5%)		206/257 (80.2%)		216/250 (86.4%)
Serious Adverse Events
	Pembrolizumab Monotherapy (Pembro Mono)		Pembrolizumab + SOC Chemotherapy (Pembro Combo)		Placebo + SOC Chemotherapy (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/254 (36.6%)		122/250 (48.8%)		117/244 (48%)
Blood and lymphatic system disorders
Anaemia	3/254 (1.2%)	3	12/250 (4.8%)	14	10/244 (4.1%)	13
Febrile neutropenia	0/254 (0%)	0	9/250 (3.6%)	9	7/244 (2.9%)	8
Hypochromic anaemia	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Iron deficiency anaemia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Neutropenia	0/254 (0%)	0	3/250 (1.2%)	3	0/244 (0%)	0
Pancytopenia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Thrombocytopenia	0/254 (0%)	0	2/250 (0.8%)	2	3/244 (1.2%)	4
Cardiac disorders
Acute myocardial infarction	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Arrhythmia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Atrial fibrillation	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Bradycardia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Cardiac arrest	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Cardiac failure	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Cardio-respiratory arrest	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Extrasystoles	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Myocardial infarction	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Myocardial ischaemia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Pericardial effusion	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Ear and labyrinth disorders
Vertigo positional	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Endocrine disorders
Addison's disease	1/254 (0.4%)	1	1/250 (0.4%)	2	0/244 (0%)	0
Adrenal insufficiency	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Hypophysitis	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Hypothyroidism	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Abdominal pain	1/254 (0.4%)	1	2/250 (0.8%)	2	2/244 (0.8%)	2
Abdominal pain lower	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Abdominal pain upper	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Ascites	1/254 (0.4%)	1	4/250 (1.6%)	5	2/244 (0.8%)	2
Colitis	1/254 (0.4%)	1	6/250 (2.4%)	6	0/244 (0%)	0
Constipation	1/254 (0.4%)	1	2/250 (0.8%)	2	0/244 (0%)	0
Diarrhoea	1/254 (0.4%)	1	7/250 (2.8%)	7	9/244 (3.7%)	9
Dysphagia	2/254 (0.8%)	2	3/250 (1.2%)	3	5/244 (2%)	6
Enterocolitis	2/254 (0.8%)	2	1/250 (0.4%)	1	1/244 (0.4%)	1
Gastric haemorrhage	5/254 (2%)	6	0/250 (0%)	0	0/244 (0%)	0
Gastric perforation	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Gastrointestinal haemorrhage	2/254 (0.8%)	2	1/250 (0.4%)	1	3/244 (1.2%)	3
Gastrointestinal obstruction	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Gastrooesophageal reflux disease	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Ileus	3/254 (1.2%)	3	0/250 (0%)	0	0/244 (0%)	0
Incarcerated hiatus hernia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Inguinal hernia	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Intestinal obstruction	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Intestinal perforation	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Large intestine perforation	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Mechanical ileus	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Melaena	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Nausea	0/254 (0%)	0	5/250 (2%)	7	5/244 (2%)	5
Obstruction gastric	2/254 (0.8%)	2	2/250 (0.8%)	2	3/244 (1.2%)	3
Oesophageal obstruction	0/254 (0%)	0	2/250 (0.8%)	3	1/244 (0.4%)	1
Pancreatitis	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Peritoneocutaneous fistula	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Salivary hypersecretion	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Small intestinal obstruction	1/254 (0.4%)	4	0/250 (0%)	0	2/244 (0.8%)	2
Stomatitis	0/254 (0%)	0	2/250 (0.8%)	2	3/244 (1.2%)	3
Subileus	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Upper gastrointestinal haemorrhage	3/254 (1.2%)	3	2/250 (0.8%)	2	2/244 (0.8%)	2
Vomiting	3/254 (1.2%)	3	6/250 (2.4%)	7	12/244 (4.9%)	15
General disorders
Asthenia	0/254 (0%)	0	3/250 (1.2%)	3	2/244 (0.8%)	2
Chest pain	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Death	6/254 (2.4%)	6	3/250 (1.2%)	3	1/244 (0.4%)	1
Fatigue	1/254 (0.4%)	1	3/250 (1.2%)	3	0/244 (0%)	0
General physical health deterioration	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Malaise	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Mucosal inflammation	0/254 (0%)	0	2/250 (0.8%)	3	3/244 (1.2%)	3
Multiple organ dysfunction syndrome	2/254 (0.8%)	2	1/250 (0.4%)	1	1/244 (0.4%)	1
Non-cardiac chest pain	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Oedema peripheral	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Pain	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Peripheral swelling	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Pyrexia	2/254 (0.8%)	2	5/250 (2%)	5	5/244 (2%)	6
Hepatobiliary disorders
Autoimmune hepatitis	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Bile duct obstruction	0/254 (0%)	0	2/250 (0.8%)	2	0/244 (0%)	0
Cholangitis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Cholangitis acute	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Cholecystitis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Hepatic cirrhosis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Hepatitis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Hyperbilirubinaemia	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Hypertransaminasaemia	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Immune-mediated hepatitis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Jaundice	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Jaundice cholestatic	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Liver disorder	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Infections and infestations
Abdominal sepsis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Amoebiasis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Appendicitis perforated	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Bacteraemia	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Biliary tract infection	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Bronchitis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Candida sepsis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Device related infection	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Endocarditis	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Enterocolitis infectious	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Gastrointestinal infection	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Infection	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Influenza	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Lower respiratory tract infection	2/254 (0.8%)	2	0/250 (0%)	0	1/244 (0.4%)	1
Lower respiratory tract infection bacterial	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Lung infection	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Meningitis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Meningitis tuberculous	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Oesophageal candidiasis	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Oral candidiasis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Pharyngitis bacterial	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Pneumonia	4/254 (1.6%)	4	6/250 (2.4%)	6	8/244 (3.3%)	10
Pneumonia bacterial	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Pneumonia klebsiella	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Prostate infection	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Pulmonary sepsis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Pulmonary tuberculosis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Respiratory tract infection	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Sepsis	0/254 (0%)	0	1/250 (0.4%)	1	4/244 (1.6%)	5
Septic shock	1/254 (0.4%)	1	1/250 (0.4%)	1	3/244 (1.2%)	3
Staphylococcal bacteraemia	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Subcutaneous abscess	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Upper respiratory tract infection	0/254 (0%)	0	2/250 (0.8%)	2	0/244 (0%)	0
Urinary tract infection	1/254 (0.4%)	1	0/250 (0%)	0	5/244 (2%)	5
Urosepsis	0/254 (0%)	0	2/250 (0.8%)	2	0/244 (0%)	0
Vascular device infection	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Wound infection	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Injury, poisoning and procedural complications
Anastomotic stenosis	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	2
Hip fracture	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Lower limb fracture	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Procedural pain	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Spinal compression fracture	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Subdural haematoma	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Subdural haemorrhage	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Toxicity to various agents	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Investigations
Aspartate aminotransferase increased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Blood bilirubin increased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Blood calcium decreased	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Blood creatinine increased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Blood magnesium decreased	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Creatinine renal clearance decreased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Hepatic enzyme increased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Transaminases increased	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Metabolism and nutrition disorders
Cachexia	2/254 (0.8%)	2	0/250 (0%)	0	1/244 (0.4%)	1
Decreased appetite	3/254 (1.2%)	3	2/250 (0.8%)	2	5/244 (2%)	5
Dehydration	1/254 (0.4%)	1	7/250 (2.8%)	8	7/244 (2.9%)	7
Diabetic ketoacidosis	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Hyperglycaemia	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Hyperkalaemia	1/254 (0.4%)	2	0/250 (0%)	0	0/244 (0%)	0
Hypocalcaemia	0/254 (0%)	0	2/250 (0.8%)	2	1/244 (0.4%)	1
Hypoglycaemia	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Hypokalaemia	1/254 (0.4%)	1	2/250 (0.8%)	2	3/244 (1.2%)	3
Hypomagnesaemia	0/254 (0%)	0	3/250 (1.2%)	3	2/244 (0.8%)	2
Hyponatraemia	5/254 (2%)	5	1/250 (0.4%)	1	2/244 (0.8%)	2
Malnutrition	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Refeeding syndrome	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Type 1 diabetes mellitus	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Type 2 diabetes mellitus	0/254 (0%)	0	1/250 (0.4%)	1	2/244 (0.8%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Back pain	1/254 (0.4%)	1	1/250 (0.4%)	1	2/244 (0.8%)	2
Compartment syndrome	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Musculoskeletal chest pain	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Myalgia	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Myositis	2/254 (0.8%)	2	0/250 (0%)	0	0/244 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	1/254 (0.4%)	1	1/250 (0.4%)	1	1/244 (0.4%)	1
Oncologic complication	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Rectal cancer	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Tumour haemorrhage	0/254 (0%)	0	2/250 (0.8%)	2	0/244 (0%)	0
Tumour pain	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Uterine cancer	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Nervous system disorders
Cerebral haemorrhage	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Cerebral infarction	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	2
Cerebral thrombosis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Cerebrovascular accident	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Dizziness	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Dizziness postural	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Embolic stroke	0/254 (0%)	0	1/250 (0.4%)	2	0/244 (0%)	0
Encephalopathy	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Epilepsy	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Intracranial venous sinus thrombosis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Ischaemic stroke	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Presyncope	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Seizure	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Syncope	0/254 (0%)	0	2/250 (0.8%)	2	3/244 (1.2%)	3
Transient ischaemic attack	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Product Issues
Device dislocation	0/254 (0%)	0	1/250 (0.4%)	3	0/244 (0%)	0
Psychiatric disorders
Completed suicide	0/254 (0%)	0	0/250 (0%)	0	2/244 (0.8%)	2
Confusional state	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Depression	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Renal and urinary disorders
Acute kidney injury	4/254 (1.6%)	4	8/250 (3.2%)	8	8/244 (3.3%)	8
Autoimmune nephritis	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Hydronephrosis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Nephritis	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Prerenal failure	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Renal failure	1/254 (0.4%)	1	3/250 (1.2%)	3	2/244 (0.8%)	2
Renal impairment	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Renal injury	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Tubulointerstitial nephritis	2/254 (0.8%)	2	0/250 (0%)	0	0/244 (0%)	0
Urinary tract obstruction	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Dyspnoea	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	1
Epistaxis	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Interstitial lung disease	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Pleural effusion	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Pneumonia aspiration	1/254 (0.4%)	1	0/250 (0%)	0	1/244 (0.4%)	2
Pneumonitis	3/254 (1.2%)	3	2/250 (0.8%)	2	1/244 (0.4%)	1
Pneumothorax	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Pulmonary embolism	2/254 (0.8%)	2	8/250 (3.2%)	9	13/244 (5.3%)	13
Respiratory arrest	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Respiratory failure	2/254 (0.8%)	2	1/250 (0.4%)	1	1/244 (0.4%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Stevens-Johnson syndrome	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Vascular disorders
Deep vein thrombosis	1/254 (0.4%)	1	2/250 (0.8%)	2	3/244 (1.2%)	3
Embolism	0/254 (0%)	0	1/250 (0.4%)	1	1/244 (0.4%)	1
Hypertension	0/254 (0%)	0	1/250 (0.4%)	1	0/244 (0%)	0
Hypotension	1/254 (0.4%)	1	1/250 (0.4%)	1	0/244 (0%)	0
Orthostatic hypotension	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Peripheral ischaemia	0/254 (0%)	0	0/250 (0%)	0	1/244 (0.4%)	1
Thrombophlebitis superficial	1/254 (0.4%)	1	0/250 (0%)	0	0/244 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab Monotherapy (Pembro Mono)		Pembrolizumab + SOC Chemotherapy (Pembro Combo)		Placebo + SOC Chemotherapy (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	214/254 (84.3%)		239/250 (95.6%)		233/244 (95.5%)
Blood and lymphatic system disorders
Anaemia	61/254 (24%)	73	112/250 (44.8%)	149	107/244 (43.9%)	142
Leukopenia	0/254 (0%)	0	21/250 (8.4%)	52	26/244 (10.7%)	51
Neutropenia	1/254 (0.4%)	2	95/250 (38%)	201	102/244 (41.8%)	222
Thrombocytopenia	2/254 (0.8%)	5	27/250 (10.8%)	38	26/244 (10.7%)	33
Ear and labyrinth disorders
Tinnitus	0/254 (0%)	0	22/250 (8.8%)	24	20/244 (8.2%)	20
Endocrine disorders
Hypothyroidism	21/254 (8.3%)	21	28/250 (11.2%)	29	10/244 (4.1%)	11
Gastrointestinal disorders
Abdominal distension	13/254 (5.1%)	21	8/250 (3.2%)	10	10/244 (4.1%)	10
Abdominal pain	46/254 (18.1%)	56	42/250 (16.8%)	50	41/244 (16.8%)	54
Abdominal pain upper	23/254 (9.1%)	26	24/250 (9.6%)	27	23/244 (9.4%)	25
Ascites	6/254 (2.4%)	7	8/250 (3.2%)	8	14/244 (5.7%)	15
Constipation	36/254 (14.2%)	43	71/250 (28.4%)	108	68/244 (27.9%)	83
Diarrhoea	35/254 (13.8%)	60	83/250 (33.2%)	153	71/244 (29.1%)	106
Dyspepsia	16/254 (6.3%)	18	13/250 (5.2%)	18	11/244 (4.5%)	13
Dysphagia	11/254 (4.3%)	11	15/250 (6%)	17	16/244 (6.6%)	20
Gastrooesophageal reflux disease	8/254 (3.1%)	8	6/250 (2.4%)	7	13/244 (5.3%)	14
Nausea	49/254 (19.3%)	59	162/250 (64.8%)	295	129/244 (52.9%)	236
Stomatitis	5/254 (2%)	6	33/250 (13.2%)	49	35/244 (14.3%)	39
Vomiting	49/254 (19.3%)	64	84/250 (33.6%)	148	79/244 (32.4%)	142
General disorders
Asthenia	30/254 (11.8%)	33	41/250 (16.4%)	53	47/244 (19.3%)	81
Chest pain	4/254 (1.6%)	6	14/250 (5.6%)	16	7/244 (2.9%)	7
Fatigue	49/254 (19.3%)	63	105/250 (42%)	156	75/244 (30.7%)	112
Mucosal inflammation	3/254 (1.2%)	5	41/250 (16.4%)	57	34/244 (13.9%)	62
Oedema peripheral	13/254 (5.1%)	14	16/250 (6.4%)	16	19/244 (7.8%)	22
Pyrexia	25/254 (9.8%)	33	32/250 (12.8%)	38	25/244 (10.2%)	26
Investigations
Alanine aminotransferase increased	13/254 (5.1%)	16	7/250 (2.8%)	8	9/244 (3.7%)	9
Aspartate aminotransferase increased	18/254 (7.1%)	22	8/250 (3.2%)	9	11/244 (4.5%)	12
Blood creatinine increased	8/254 (3.1%)	8	30/250 (12%)	52	34/244 (13.9%)	58
Neutrophil count decreased	4/254 (1.6%)	12	59/250 (23.6%)	119	40/244 (16.4%)	79
Platelet count decreased	3/254 (1.2%)	3	23/250 (9.2%)	38	17/244 (7%)	21
Weight decreased	28/254 (11%)	28	54/250 (21.6%)	63	33/244 (13.5%)	33
White blood cell count decreased	4/254 (1.6%)	6	30/250 (12%)	71	25/244 (10.2%)	52
Metabolism and nutrition disorders
Decreased appetite	48/254 (18.9%)	53	93/250 (37.2%)	134	90/244 (36.9%)	127
Dehydration	7/254 (2.8%)	7	11/250 (4.4%)	14	16/244 (6.6%)	19
Hypoalbuminaemia	18/254 (7.1%)	21	17/250 (6.8%)	21	23/244 (9.4%)	28
Hypocalcaemia	9/254 (3.5%)	10	14/250 (5.6%)	20	14/244 (5.7%)	16
Hypokalaemia	11/254 (4.3%)	16	35/250 (14%)	49	42/244 (17.2%)	62
Hypomagnesaemia	3/254 (1.2%)	11	34/250 (13.6%)	43	32/244 (13.1%)	48
Hyponatraemia	15/254 (5.9%)	16	12/250 (4.8%)	21	20/244 (8.2%)	26
Hypophosphataemia	2/254 (0.8%)	2	15/250 (6%)	21	9/244 (3.7%)	15
Musculoskeletal and connective tissue disorders
Arthralgia	15/254 (5.9%)	15	17/250 (6.8%)	20	6/244 (2.5%)	6
Back pain	30/254 (11.8%)	32	13/250 (5.2%)	14	14/244 (5.7%)	15
Pain in extremity	4/254 (1.6%)	4	17/250 (6.8%)	23	8/244 (3.3%)	9
Nervous system disorders
Dizziness	14/254 (5.5%)	18	20/250 (8%)	21	15/244 (6.1%)	22
Dysgeusia	6/254 (2.4%)	6	24/250 (9.6%)	26	26/244 (10.7%)	29
Headache	16/254 (6.3%)	18	24/250 (9.6%)	26	16/244 (6.6%)	22
Neuropathy peripheral	0/254 (0%)	0	31/250 (12.4%)	36	16/244 (6.6%)	17
Peripheral sensory neuropathy	3/254 (1.2%)	3	34/250 (13.6%)	37	16/244 (6.6%)	18
Psychiatric disorders
Insomnia	21/254 (8.3%)	21	18/250 (7.2%)	19	21/244 (8.6%)	23
Respiratory, thoracic and mediastinal disorders
Cough	19/254 (7.5%)	23	24/250 (9.6%)	26	23/244 (9.4%)	26
Dyspnoea	11/254 (4.3%)	16	19/250 (7.6%)	23	9/244 (3.7%)	11
Hiccups	1/254 (0.4%)	1	16/250 (6.4%)	20	12/244 (4.9%)	21
Skin and subcutaneous tissue disorders
Alopecia	2/254 (0.8%)	2	19/250 (7.6%)	19	11/244 (4.5%)	11
Dry skin	6/254 (2.4%)	6	15/250 (6%)	16	15/244 (6.1%)	15
Palmar-plantar erythrodysaesthesia syndrome	0/254 (0%)	0	60/250 (24%)	69	46/244 (18.9%)	57
Pruritus	22/254 (8.7%)	27	20/250 (8%)	23	8/244 (3.3%)	11
Rash	20/254 (7.9%)	23	30/250 (12%)	39	14/244 (5.7%)	17

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. Sponsor review can be expedited to meet publication timelines.