Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal/ Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)

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ClinicalTrials.gov Identifier: NCT02564263

Recruitment Status : Completed

First Posted : September 30, 2015

Results First Posted : November 20, 2019

Last Update Posted : March 13, 2023

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Merck Sharp & Dohme LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Esophageal Carcinoma Esophagogastric Junction Carcinoma
Interventions	Biological: pembrolizumab Drug: paclitaxel Drug: docetaxel Drug: irinotecan
Enrollment	628

Participant Flow

Recruitment Details
Pre-assignment Details	At the time of the primary analysis data cut-off of 15-Oct-2018, 67 participants were ongoing in the study.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description	Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Period Title: Overall Study
Started	314	314
Treated	314	296
Received Second Course of Pembrolizumab	5	0
Completed	0	0
Not Completed	314	314
Reason Not Completed
Adverse Event	31	29
Death	270	262
Withdrawal by Subject	4	19
Sponsor's decision	9	4

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Chemotherapy	Total
Arm/Group Description		Participants received pembrolizumab...	Participants received Investigator'...	Total of all reporting groups
Arm/Group Description		Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).	Total of all reporting groups
Overall Number of Baseline Participants		314	314	628
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	314 participants	314 participants	628 participants
		62.6 (9.4)	62.0 (9.6)	62.3 (9.5)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	Female	41 13.1%	43 13.7%	84 13.4%
	Male	273 86.9%	271 86.3%	544 86.6%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	Hispanic or Latino	19 6.1%	25 8.0%	44 7.0%
	Not Hispanic or Latino	288 91.7%	273 86.9%	561 89.3%
	Unknown or Not Reported	7 2.2%	16 5.1%	23 3.7%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	American Indian or Alaska Native	0 0.0%	1 0.3%	1 0.2%
	Asian	126 40.1%	122 38.9%	248 39.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 0.3%	1 0.2%
	Black or African American	3 1.0%	3 1.0%	6 1.0%
	White	179 57.0%	172 54.8%	351 55.9%
	More than one race	2 0.6%	4 1.3%	6 1.0%
	Unknown or Not Reported	4 1.3%	11 3.5%	15 2.4%
Programmed Death-Ligand 1 (PD-L1) Status: Combined Positive Score (CPS) ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	PD-L1 CPS ≥10	109 34.7%	117 37.3%	226 36.0%
	PD-L1 CPS <10	199 63.4%	194 61.8%	393 62.6%
	Not Evaluable	6 1.9%	3 1.0%	9 1.4%
		[1] Measure Description: Participants were assessed for their PD-L1 tumor expression levels by immunohistochemistry assay on tumor tissue from a newly obtained biopsy. PD-L1 CPS was calculated as the number of PD-L1 positive cells (tumor cells, macrophages, lymphocytes) divided by the total tumor cells and is expressed as a percentage. Participants were classified based on their PD-L1 tumor status as being either PD-L1 CPS ≥10 or PD-L1 CPS <10.
Geographic Region ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	Asia	121 38.5%	122 38.9%	243 38.7%
	RoW	193 61.5%	192 61.1%	385 61.3%
		[1] Measure Description: Participants were classified based on their geographic region of enrollment as either being from Asia or from outside of Asia (Rest of World [RoW]).
Tumor Histology ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	314 participants	314 participants	628 participants
	Squamous cell carcinoma	199 63.4%	204 65.0%	403 64.2%
	Adenocarcinoma of esophagus & EGJ Siewert type I	115 36.6%	110 35.0%	225 35.8%
		[1] Measure Description: Participants were classified based on their tumor histology (cell type) as either having squamous cell carcinoma or having adenocarcinoma of esophagus and esophagogastric junction (EGJ) Siewert type I.

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Description	OS was defined as the time from randomization to death due to any caus...
Description	OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	198	203
Median (95% Confidence Interval) Unit of Measure: Months
	8.2 (6.7 to 10.3)	7.1 (6.1 to 8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00894
	Comments	One-sided p-value based on stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.63 to 0.96
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW)

2.Primary Outcome


Title	Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Description	OS was defined as the time from randomization to death due to any caus...
Description	OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	107	115
Median (95% Confidence Interval) Unit of Measure: Months
	9.3 (6.6 to 12.5)	6.7 (5.1 to 8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00855
	Comments	One-sided p-value based on stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.52 to 0.94
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ])

3.Primary Outcome


Title	Overall Survival (OS) in All Participants
Description	OS was defined as the time from randomization to death due to any caus...
Description	OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	314	314
Median (95% Confidence Interval) Unit of Measure: Months
	7.1 (6.2 to 8.1)	7.1 (6.3 to 8.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0531
	Comments	One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.75 to 1.05
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ])

4.Secondary Outcome


Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Description	PFS was defined as the time from randomization to the first documented...
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 in all participants is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	314	314
Median (95% Confidence Interval) Unit of Measure: Months
	2.1 (2.1 to 2.2)	3.4 (2.8 to 3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.287
	Comments	One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95% 0.94 to 1.31
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ)

5.Secondary Outcome


Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Description	ORR was defined as the percentage of participants who had a Complete R...
Description	ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of all participants who experienced a CR or PR is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	314	314
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	13.1 (9.5 to 17.3)	6.7 (4.2 to 10.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0037
	Comments	One-sided p-value for testing. H0: difference in %=0 versus; H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 95% 1.7 to 11.2
	Estimation Comments	Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ)

6.Secondary Outcome


Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Description	PFS was defined as the time from randomization to the first documented...
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	198	203
Median (95% Confidence Interval) Unit of Measure: Months
	2.2 (2.1 to 3.2)	3.1 (2.2 to 3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.216
	Comments	One-sided p-value based on stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95% 0.75 to 1.13
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW)

7.Secondary Outcome


Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Description	PFS was defined as the time from randomization to the first documented...
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	107	115
Median (95% Confidence Interval) Unit of Measure: Months
	2.6 (2.1 to 4.1)	3.0 (2.1 to 3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.015
	Comments	One-sided p-value based on stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.54 to 0.97
	Estimation Comments	Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ)

8.Secondary Outcome


Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Description	ORR was defined as the percentage of participants who had a Complete R...
Description	ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	198	203
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	16.7 (11.8 to 22.6)	7.4 (4.2 to 11.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0022
	Comments	One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	9.2
	Confidence Interval	(2-Sided) 95% 3.0 to 15.8
	Estimation Comments	Miettinen & Nurminen method stratified by geographic region (Asia vs RoW)

9.Secondary Outcome


Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Description	ORR was defined as the percentage of participants who had a Complete R...
Description	ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
Time Frame	Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	107	115
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	21.5 (14.1 to 30.5)	6.1 (2.5 to 12.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0006
	Comments	One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	15.1
	Confidence Interval	(2-Sided) 95% 6.2 to 24.7
	Estimation Comments	Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ)

10.Secondary Outcome


Title	Number of Participants Experiencing an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant ...
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to 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 AE. The number of participants who experienced ≥1 AE is presented.
Time Frame	Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	314	296
Measure Type: Count of Participants Unit of Measure: Participants
	301 95.9%	288 97.3%

11.Secondary Outcome


Title	Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant ...
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to 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 AE. The number of participants who discontinued study treatment due to an AE is presented.
Time Frame	Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were included in the treatment group to which they were randomized.


Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description:	Participants received pembrolizumab...	Participants received Investigator'...
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).	Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Overall Number of Participants Analyzed	314	296
Measure Type: Count of Participants Unit of Measure: Participants
	40 12.7%	42 14.2%

Adverse Events

Time Frame	Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
Adverse Event Reporting Description	All-Cause Mortality (ACM) was reported for all randomized participants. Five participants got a second course of pembrolizumab and were monitored for AEs and ACM. Safety was analyzed in participants who got ≥1 dose of study drug. Per protocol, disease progression of cancer was not considered an AE unless considered related to study drug. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to study drug are excluded as AEs.

Arm/Group Title	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
Arm/Group Description	Participants received pembrolizumab...		Participants received Investigator'...		Qualified participants who received...
Arm/Group Description	Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).		Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).		Qualified participants who received pembrolizumab as a first course and stopped the first course of pembrolizumab due to complete response (CR) or completed the first course of pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (approximately 1 year additional).
All-Cause Mortality
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	305/314 (97.13%)		305/314 (97.13%)		3/5 (60.00%)
Serious Adverse Events Serious Adverse Events
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	127/314 (40.45%)		121/296 (40.88%)		1/5 (20.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/314 (0.64%)	2	5/296 (1.69%)	5	0/5 (0.00%)	0
Febrile neutropenia ^† 1	1/314 (0.32%)	1	22/296 (7.43%)	24	0/5 (0.00%)	0
Immune thrombocytopenia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Leukopenia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Neutropenia ^† 1	0/314 (0.00%)	0	4/296 (1.35%)	5	0/5 (0.00%)	0
Cardiac disorders
Acute left ventricular failure ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Acute myocardial infarction ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Atrial fibrillation ^† 1	2/314 (0.64%)	3	2/296 (0.68%)	2	0/5 (0.00%)	0
Cardio-respiratory arrest ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Myocarditis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Sinus tachycardia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Tachycardia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Endocrine disorders
Hypercalcaemia of malignancy ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hypophysitis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Inappropriate antidiuretic hormone secretion ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Eye disorders
Cataract ^† 1	1/314 (0.32%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Gastrointestinal disorders
Abdominal distension ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Abdominal pain ^† 1	3/314 (0.96%)	3	1/296 (0.34%)	1	0/5 (0.00%)	0
Colitis ^† 1	3/314 (0.96%)	3	0/296 (0.00%)	0	0/5 (0.00%)	0
Constipation ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Diarrhoea ^† 1	1/314 (0.32%)	1	4/296 (1.35%)	4	0/5 (0.00%)	0
Diverticulum oesophageal ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Dysphagia ^† 1	11/314 (3.50%)	12	1/296 (0.34%)	1	0/5 (0.00%)	0
Enterocolitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	2/314 (0.64%)	2	4/296 (1.35%)	4	0/5 (0.00%)	0
Gastrointestinal hypomotility ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Haematemesis ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Impaired gastric emptying ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Intestinal perforation ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Nausea ^† 1	1/314 (0.32%)	1	3/296 (1.01%)	3	0/5 (0.00%)	0
Oesophageal fistula ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Oesophageal haemorrhage ^† 1	4/314 (1.27%)	4	0/296 (0.00%)	0	0/5 (0.00%)	0
Oesophageal obstruction ^† 1	3/314 (0.96%)	3	1/296 (0.34%)	1	0/5 (0.00%)	0
Oesophageal perforation ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Oesophageal stenosis ^† 1	2/314 (0.64%)	2	1/296 (0.34%)	1	0/5 (0.00%)	0
Oesophageal ulcer ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Oesophagitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Peritoneal adhesions ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Upper gastrointestinal haemorrhage ^† 1	0/314 (0.00%)	0	3/296 (1.01%)	3	0/5 (0.00%)	0
Vomiting ^† 1	2/314 (0.64%)	2	5/296 (1.69%)	5	0/5 (0.00%)	0
General disorders
Asthenia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Chest pain ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Death ^† 1	5/314 (1.59%)	5	10/296 (3.38%)	10	0/5 (0.00%)	0
Fatigue ^† 1	2/314 (0.64%)	2	2/296 (0.68%)	2	0/5 (0.00%)	0
General physical health deterioration ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Pyrexia ^† 1	4/314 (1.27%)	4	4/296 (1.35%)	4	0/5 (0.00%)	0
Strangulated hernia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	3/314 (0.96%)	3	0/296 (0.00%)	0	0/5 (0.00%)	0
Cholecystitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Cholecystitis acute ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Hepatic failure ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Hepatic function abnormal ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Immune-mediated hepatitis ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Liver injury ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Infections and infestations
Appendicitis ^† 1	0/314 (0.00%)	0	2/296 (0.68%)	2	0/5 (0.00%)	0
Bacteraemia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Beta haemolytic streptococcal infection ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Bronchitis ^† 1	1/314 (0.32%)	1	2/296 (0.68%)	2	0/5 (0.00%)	0
Candida infection ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Cellulitis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Clostridium difficile colitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Device related sepsis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Empyema ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hepatic infection ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Herpes zoster ^† 1	1/314 (0.32%)	1	2/296 (0.68%)	2	0/5 (0.00%)	0
Infection ^† 1	0/314 (0.00%)	0	2/296 (0.68%)	2	0/5 (0.00%)	0
Liver abscess ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Lower respiratory tract infection viral ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Mediastinitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Peritonitis ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Pneumonia ^† 1	14/314 (4.46%)	15	22/296 (7.43%)	26	0/5 (0.00%)	0
Pneumonia aspiration ^† 1	12/314 (3.82%)	13	5/296 (1.69%)	5	0/5 (0.00%)	0
Pneumonia bacterial ^† 1	0/314 (0.00%)	0	2/296 (0.68%)	2	0/5 (0.00%)	0
Pneumonia necrotising ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Pulmonary sepsis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Respiratory tract infection ^† 1	3/314 (0.96%)	3	2/296 (0.68%)	2	0/5 (0.00%)	0
Sepsis ^† 1	4/314 (1.27%)	4	3/296 (1.01%)	4	0/5 (0.00%)	0
Septic shock ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Stoma site infection ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Subcutaneous abscess ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Tracheitis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Tracheostomy infection ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Upper respiratory tract infection ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Urinary tract infection ^† 1	2/314 (0.64%)	2	1/296 (0.34%)	1	0/5 (0.00%)	0
Varicella zoster virus infection ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Vascular device infection ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Injury, poisoning and procedural complications
Anastomotic fistula ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Anastomotic leak ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Fall ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Femoral neck fracture ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Foreign body in gastrointestinal tract ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Gastrostomy failure ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Infusion related reaction ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Radiation pneumonitis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Spinal compression fracture ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Subdural haematoma ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Tracheal injury ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Tracheal obstruction ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Upper limb fracture ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Investigations
Hepatic enzyme increased ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Liver function test increased ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Neutrophil count decreased ^† 1	1/314 (0.32%)	1	3/296 (1.01%)	3	0/5 (0.00%)	0
Weight decreased ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
White blood cell count decreased ^† 1	1/314 (0.32%)	1	2/296 (0.68%)	2	0/5 (0.00%)	0
White blood cell count increased ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/314 (0.64%)	2	2/296 (0.68%)	2	0/5 (0.00%)	0
Dehydration ^† 1	2/314 (0.64%)	2	4/296 (1.35%)	4	0/5 (0.00%)	0
Electrolyte imbalance ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hypercalcaemia ^† 1	3/314 (0.96%)	3	0/296 (0.00%)	0	0/5 (0.00%)	0
Hyperglycaemia ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Hypoglycaemia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hypokalaemia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hyponatraemia ^† 1	0/314 (0.00%)	0	2/296 (0.68%)	2	0/5 (0.00%)	0
Hypophosphataemia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Type 1 diabetes mellitus ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Back pain ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Fistula inflammation ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Neck pain ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Polymyositis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Cancer pain ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Head and neck cancer ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Metastases to bone ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Squamous cell carcinoma ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Nervous system disorders
Bell's palsy ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Cerebellar stroke ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Cerebral infarction ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Cerebrovascular accident ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Demyelination ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Dyskinesia ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Dystonia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Facial paralysis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Guillain-Barre syndrome ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Haemorrhage intracranial ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Haemorrhagic stroke ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Headache ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Hemiparesis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Neuralgia ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Neuropathy peripheral ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Radiculopathy ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Spinal cord compression ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Vocal cord paralysis ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Product Issues
Device dislocation ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Device occlusion ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Psychiatric disorders
Completed suicide ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Confusional state ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Delirium ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	2/314 (0.64%)	2	1/296 (0.34%)	1	0/5 (0.00%)	0
Chronic kidney disease ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Reproductive system and breast disorders
Prostatitis ^† 1	0/314 (0.00%)	0	0/296 (0.00%)	0	1/5 (20.00%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Acute respiratory failure ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Aspiration ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Dyspnoea ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Haemoptysis ^† 1	2/314 (0.64%)	2	0/296 (0.00%)	0	0/5 (0.00%)	0
Hiccups ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Interstitial lung disease ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Lung disorder ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Pleural effusion ^† 1	1/314 (0.32%)	2	2/296 (0.68%)	2	0/5 (0.00%)	0
Pneumonitis ^† 1	7/314 (2.23%)	7	0/296 (0.00%)	0	0/5 (0.00%)	0
Pneumothorax ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	0/5 (0.00%)	0
Pulmonary embolism ^† 1	3/314 (0.96%)	3	0/296 (0.00%)	0	0/5 (0.00%)	0
Pulmonary necrosis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Respiratory failure ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Stridor ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Tracheal fistula ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Upper airway obstruction ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Skin and subcutaneous tissue disorders
Dermal cyst ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Vascular disorders
Deep vein thrombosis ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	0/5 (0.00%)	0
Haemorrhage ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
Shock haemorrhagic ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	0/5 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	285/314 (90.76%)		281/296 (94.93%)		5/5 (100.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	52/314 (16.56%)	60	83/296 (28.04%)	110	1/5 (20.00%)	2
Neutropenia ^† 1	0/314 (0.00%)	0	36/296 (12.16%)	65	0/5 (0.00%)	0
Endocrine disorders
Hypothyroidism ^† 1	37/314 (11.78%)	40	7/296 (2.36%)	7	1/5 (20.00%)	1
Gastrointestinal disorders
Abdominal distension ^† 1	7/314 (2.23%)	7	2/296 (0.68%)	2	1/5 (20.00%)	1
Abdominal pain ^† 1	34/314 (10.83%)	36	27/296 (9.12%)	32	0/5 (0.00%)	0
Abdominal pain upper ^† 1	14/314 (4.46%)	16	17/296 (5.74%)	19	0/5 (0.00%)	0
Constipation ^† 1	56/314 (17.83%)	63	56/296 (18.92%)	63	0/5 (0.00%)	0
Diarrhoea ^† 1	38/314 (12.10%)	65	79/296 (26.69%)	120	1/5 (20.00%)	1
Dyspepsia ^† 1	6/314 (1.91%)	7	11/296 (3.72%)	13	1/5 (20.00%)	1
Dysphagia ^† 1	40/314 (12.74%)	44	26/296 (8.78%)	27	1/5 (20.00%)	1
Nausea ^† 1	59/314 (18.79%)	66	83/296 (28.04%)	110	0/5 (0.00%)	0
Stomatitis ^† 1	9/314 (2.87%)	9	28/296 (9.46%)	30	0/5 (0.00%)	0
Vomiting ^† 1	37/314 (11.78%)	45	53/296 (17.91%)	74	0/5 (0.00%)	0
General disorders
Asthenia ^† 1	45/314 (14.33%)	48	43/296 (14.53%)	58	0/5 (0.00%)	0
Fatigue ^† 1	67/314 (21.34%)	70	87/296 (29.39%)	121	0/5 (0.00%)	0
Malaise ^† 1	15/314 (4.78%)	18	19/296 (6.42%)	26	0/5 (0.00%)	0
Oedema peripheral ^† 1	19/314 (6.05%)	20	19/296 (6.42%)	19	0/5 (0.00%)	0
Pyrexia ^† 1	31/314 (9.87%)	41	45/296 (15.20%)	58	0/5 (0.00%)	0
Infections and infestations
Upper respiratory tract infection ^† 1	12/314 (3.82%)	17	13/296 (4.39%)	15	1/5 (20.00%)	2
Investigations
Alanine aminotransferase increased ^† 1	22/314 (7.01%)	26	10/296 (3.38%)	16	0/5 (0.00%)	0
Aspartate aminotransferase increased ^† 1	26/314 (8.28%)	33	14/296 (4.73%)	16	1/5 (20.00%)	1
Blood creatinine increased ^† 1	8/314 (2.55%)	11	3/296 (1.01%)	4	1/5 (20.00%)	1
Blood sodium decreased ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	1/5 (20.00%)	1
Blood thyroid stimulating hormone increased ^† 1	3/314 (0.96%)	4	3/296 (1.01%)	3	1/5 (20.00%)	1
Lymphocyte count decreased ^† 1	9/314 (2.87%)	10	9/296 (3.04%)	15	1/5 (20.00%)	1
Neutrophil count decreased ^† 1	2/314 (0.64%)	2	50/296 (16.89%)	113	0/5 (0.00%)	0
Weight decreased ^† 1	39/314 (12.42%)	39	34/296 (11.49%)	43	1/5 (20.00%)	1
White blood cell count decreased ^† 1	1/314 (0.32%)	1	52/296 (17.57%)	114	0/5 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	76/314 (24.20%)	82	76/296 (25.68%)	97	1/5 (20.00%)	1
Gout ^† 1	1/314 (0.32%)	1	0/296 (0.00%)	0	1/5 (20.00%)	1
Hyperglycaemia ^† 1	16/314 (5.10%)	21	14/296 (4.73%)	14	0/5 (0.00%)	0
Hyperkalaemia ^† 1	8/314 (2.55%)	13	6/296 (2.03%)	7	1/5 (20.00%)	1
Hypoalbuminaemia ^† 1	17/314 (5.41%)	23	15/296 (5.07%)	16	0/5 (0.00%)	0
Hypokalaemia ^† 1	15/314 (4.78%)	15	29/296 (9.80%)	40	0/5 (0.00%)	0
Hyponatraemia ^† 1	19/314 (6.05%)	27	17/296 (5.74%)	24	0/5 (0.00%)	0
Iron deficiency ^† 1	1/314 (0.32%)	1	1/296 (0.34%)	1	1/5 (20.00%)	1
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	24/314 (7.64%)	26	19/296 (6.42%)	22	0/5 (0.00%)	0
Back pain ^† 1	38/314 (12.10%)	40	24/296 (8.11%)	27	0/5 (0.00%)	0
Myalgia ^† 1	8/314 (2.55%)	10	25/296 (8.45%)	31	0/5 (0.00%)	0
Pain in extremity ^† 1	8/314 (2.55%)	10	8/296 (2.70%)	9	1/5 (20.00%)	1
Nervous system disorders
Dementia Alzheimer's type ^† 1	0/314 (0.00%)	0	0/296 (0.00%)	0	1/5 (20.00%)	1
Neuropathy peripheral ^† 1	6/314 (1.91%)	7	25/296 (8.45%)	28	0/5 (0.00%)	0
Peripheral sensory neuropathy ^† 1	3/314 (0.96%)	3	52/296 (17.57%)	53	0/5 (0.00%)	0
Psychiatric disorders
Insomnia ^† 1	25/314 (7.96%)	25	16/296 (5.41%)	42	0/5 (0.00%)	0
Irritability ^† 1	0/314 (0.00%)	0	1/296 (0.34%)	1	1/5 (20.00%)	1
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	40/314 (12.74%)	46	30/296 (10.14%)	33	0/5 (0.00%)	0
Dyspnoea ^† 1	31/314 (9.87%)	36	17/296 (5.74%)	21	0/5 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia ^† 1	4/314 (1.27%)	4	88/296 (29.73%)	88	0/5 (0.00%)	0
Pruritus ^† 1	23/314 (7.32%)	27	8/296 (2.70%)	8	1/5 (20.00%)	1
Rash ^† 1	20/314 (6.37%)	24	25/296 (8.45%)	27	0/5 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this study 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.

Results Point of Contact

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Name/Title:	Senior Vice President, Global Clinical Development
Organization:	Merck Sharp & Dohme LLC
Phone:	1-800-672-6372
EMail:	ClinicalTrialsDisclosure@merck.com

Publications of Results:

Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. doi: 10.1200/JCO.20.01888. Epub 2020 Oct 7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb 1;40(4):382-391. doi: 10.1200/JCO.21.00601. Epub 2021 Nov 3.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT02564263
Other Study ID Numbers:	3475-181 163145 ( Registry Identifier: JAPAN-CTI ) MK-3475-181 ( Other Identifier: Merck ) KEYNOTE-181 ( Other Identifier: Merck ) 2015-002782-32 ( EudraCT Number )
First Submitted:	September 29, 2015
First Posted:	September 30, 2015
Results First Submitted:	September 26, 2019
Results First Posted:	November 20, 2019
Last Update Posted:	March 13, 2023

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