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

• ClinicalTrials.gov Identifier: NCT02335411
• Recruitment Status: Completed
• First Posted: January 9, 2015
• Results First Posted: August 8, 2022
• Last Update Posted: August 8, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Gastric Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma
• Interventions: Biological: pembrolizumab; Drug: cisplatin; Drug: 5-FU; Drug: capecitabine
• Enrollment: 318

Participant Flow

Recruitment Details	Male and female participants of at least 18 years of age with recurrent or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma were enrolled in this study.
Pre-assignment Details	318 participants were originally allocated to the study. No study information was collected from 3 participants, who were excluded from all analyses, including disposition. Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures respectively.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Period Title: Overall Study
Started [1]	259	25	31
Second Course Pembrolizumab	3	1	2
Completed	0	0	0
Not Completed	259	25	31
Reason Not Completed
Death	223	22	26
Physician Decision	3	0	0
Protocol Violation	1	0	0
Withdrawal by Subject	11	0	3
Sponsor Decision	12	3	2
Adverse Event	9	0	0
[1] First Course Pembrolizumab

Baseline Characteristics

Arm/Group Title		Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	Total
Arm/Group Description		Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Total of all reporting groups
Overall Number of Baseline Participants		259	25	31	315
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	259 participants	25 participants	31 participants	315 participants
		61.0 (11.4)	58.8 (16.6)	60.3 (11.2)	60.7 (11.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	25 participants	31 participants	315 participants
	Female	61 23.6%	9 36.0%	12 38.7%	82 26.0%
	Male	198 76.4%	16 64.0%	19 61.3%	233 74.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	25 participants	31 participants	315 participants
	Hispanic or Latino	17 6.6%	1 4.0%	3 9.7%	21 6.7%
	Not Hispanic or Latino	228 88.0%	23 92.0%	28 90.3%	279 88.6%
	Unknown or Not Reported	14 5.4%	1 4.0%	0 0.0%	15 4.8%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	25 participants	31 participants	315 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	41 15.8%	17 68.0%	15 48.4%	73 23.2%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 1.9%	0 0.0%	0 0.0%	5 1.6%
	White	200 77.2%	8 32.0%	16 51.6%	224 71.1%
	More than one race	2 0.8%	0 0.0%	0 0.0%	2 0.6%
	Unknown or Not Reported	11 4.2%	0 0.0%	0 0.0%	11 3.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	25	31
Measure Type: Count of Participants; Unit of Measure: Participants
	248 95.8%	25 100.0%	31 100.0%

2. Primary Outcome

Title	Number of Participants Discontinuing Study Drug Due to AEs
Description	An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinued study drug due to an AE is presented. Per protocol, the number of participants who discontinued drug during first course pembrolizumab treatment is presented.
Time Frame	Up to approximately 52 months

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	25	31
Measure Type: Count of Participants; Unit of Measure: Participants
	18 6.9%	4 16.0%	0 0.0%

3. Primary Outcome

Title	Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3
Description	The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of programmed death-ligand 1 [PD-L1] tumor status) in Cohorts 1 and 3 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants in Cohorts 1 and 3 who received ≥1 dose of study drug. Per protocol, Cohort 2 was not included in this outcome measure.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	0	31
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	11.6; (8.0 to 16.1)		22.6; (9.6 to 41.1)

4. Primary Outcome

Title	Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3
Description	The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of all participants in Cohorts 1 and 3 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants in Cohorts 1 and 3 with a positive PD-L1 tumor status who received ≥1 dose of study drug. Per protocol, Cohort 2 was not included in this outcome measure.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	148	0	31
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	15.5; (10.1 to 22.4)		22.6; (9.6 to 41.1)

5. Secondary Outcome

Title	Objective Response Rate (ORR) For All Participants in Cohort 2
Description	The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) in Cohort 2 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants in Cohort 2 who received ≥1 dose of study drug. Per protocol, Cohorts 1 and 3 were not included in this outcome measure.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	0	25	0
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
		60.0; (38.7 to 78.9)

6. Secondary Outcome

Title	Objective Response Rate For PD-L1 Positive Participants in Cohort 2
Description	The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of participants in Cohort 2 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants in Cohort 2 with a positive PD-L1 tumor status who received ≥1 dose of study drug. Per protocol, Cohorts 1 and 3 were not included in this outcome measure.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	0	15	0
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
		73.3; (44.9 to 92.2)

7. Secondary Outcome

Title	Duration of Response (DOR) For All Participants
Description	Duration of Response (DOR) was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug and demonstrated a confirmed response (CR or PR).

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	30	15	7
Median (Full Range); Unit of Measure: Months
	16.1 [1]; (2.4 to NA)	4.6 [1]; (2.6 to NA)	38.0 [1]; (2.1 to NA)

[1]

NA = upper limit not reached at time of data cut-off due to insufficient number of responding participants with relapse.

8. Secondary Outcome

Title	Duration of Response For PD-L1 Positive Participants
Description	DOR was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug and demonstrated a confirmed response (CR or PR).

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	23	11	7
Median (Full Range); Unit of Measure: Months
	NA [1]; (NA to NA)	4.6 [2]; (3.2 to NA)	38.0 [2]; (2.1 to NA)

[1]

NA = median, upper and lower limits not reached at time of data cut-off due to insufficient number of responding participants with relapse.

[2]

NA = upper limit not reached at time of data cut-off due to insufficient number of responding participants with relapse.

9. Secondary Outcome

Title	Progression-Free Survival (PFS) For All Participants
Description	Progression-Free Survival (PFS) was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	25	31
Median (95% Confidence Interval); Unit of Measure: Months
	2.0; (2.0 to 2.0)	6.6; (5.9 to 10.6)	2.9; (2.0 to 6.0)

10. Secondary Outcome

Title	Progression-Free Survival For PD-L1 Positive Participants
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The PFS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	148	15	31
Median (95% Confidence Interval); Unit of Measure: Months
	2.1; (2.0 to 2.1)	6.5; (4.7 to 7.9)	2.9; (2.0 to 6.0)

11. Secondary Outcome

Title	Overall Survival (OS) For All Participants
Description	Overall Survival (OS) was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	25	31
Median (95% Confidence Interval); Unit of Measure: Months
	5.5; (4.2 to 6.7)	13.8; (8.6 to 25.6)	20.7; (10.0 to 29.8)

12. Secondary Outcome

Title	Overall Survival For PD-L1 Positive Participants
Description	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	148	15	31
Median (95% Confidence Interval); Unit of Measure: Months
	5.8; (4.4 to 7.8)	11.1; (5.4 to 22.3)	20.7; (10.0 to 29.8)

13. Secondary Outcome

Title	Disease Control Rate (DCR) For All Participants
Description	Disease Control Rate (DCR) was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) who had a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	259	25	31
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	27.0; (21.7 to 32.9)	80.0; (59.3 to 93.2)	32.3; (16.7 to 51.4)

14. Secondary Outcome

Title	Disease Control Rate For PD-L1 Positive Participants
Description	DCR was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of participants with PD-L1+ tumor status who experienced a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Time Frame	Up to approximately 75 months

Outcome Measure Data

Analysis Population Description

All enrolled participants with a positive PD-L1 tumor status who received ≥1 dose of study drug.

Arm/Group Title	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive
Arm/Group Description:	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.
Overall Number of Participants Analyzed	148	15	31
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	33.1; (25.6 to 41.3)	80.0; (51.9 to 95.7)	32.3; (16.7 to 51.4)

Adverse Events

Time Frame	Up to approximately 75 months
Adverse Event Reporting Description	The population analyzed for all-cause mortality consisted of all allocated participants. The population for AEs consisted of all allocated participants who received ≥1 dose of study drug. Per protocol disease progression of cancer was not considered an AE unless related to study drug. Therefore the following AE preferred terms not related to the drug were excluded: Neoplasm progression, Malignant neoplasm progression and Disease progression.
Arm/Group Title	Cohort 1 First Course		Cohort 2 First Course		Cohort 3 First Course		Cohort 1 Second Course		Cohort 2 Second Course		Cohort 3 Second Course
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months.		Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m^2 IV Q3W for up to 6 cycles + 5-FU 800 mg/m^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m^2 orally, BID on Days 1-14 of each 3-week cycle.		PD-L1 positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months		Eligible participants allocated to the pembrolizumab first course in Cohort 1 who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year.		Eligible participants allocated to the pembrolizumab first course in Cohort 2 who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year.		Eligible participants allocated to the pembrolizumab first course in Cohort 3 who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year.
All-Cause Mortality
	Cohort 1 First Course		Cohort 2 First Course		Cohort 3 First Course		Cohort 1 Second Course		Cohort 2 Second Course		Cohort 3 Second Course
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	244/259 (94.21%)		21/25 (84.00%)		26/31 (83.87%)		1/3 (33.33%)		1/1 (100.00%)		1/2 (50.00%)
Serious Adverse Events
	Cohort 1 First Course		Cohort 2 First Course		Cohort 3 First Course		Cohort 1 Second Course		Cohort 2 Second Course		Cohort 3 Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	119/259 (45.95%)		11/25 (44.00%)		15/31 (48.39%)		0/3 (0.00%)		0/1 (0.00%)		0/2 (0.00%)
Blood and lymphatic system disorders
Abdominal lymphadenopathy † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Anaemia † 1	6/259 (2.32%)	6	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cardiac disorders
Atrial fibrillation † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cardiac arrest † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cardiac tamponade † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Myocardial infarction † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pericardial effusion † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Supraventricular tachycardia † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Endocrine disorders
Hypothyroidism † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Thyroiditis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Eye disorders
Diffuse uveal melanocytic proliferation † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	4/259 (1.54%)	4	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Abdominal pain upper † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Ascites † 1	2/259 (0.77%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Colitis † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Constipation † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Diarrhoea † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Diverticulum intestinal haemorrhagic † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dysphagia † 1	7/259 (2.70%)	7	1/25 (4.00%)	1	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Enterocolitis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastric haemorrhage † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastric perforation † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastric stenosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastrointestinal haemorrhage † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Haematemesis † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Ileus † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Intestinal obstruction † 1	6/259 (2.32%)	6	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Jejunal perforation † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Large intestinal obstruction † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Melaena † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Nausea † 1	5/259 (1.93%)	7	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Obstruction gastric † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oesophageal intramural haematoma † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oesophageal perforation † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oesophageal stenosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oesophageal ulcer † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Small intestinal obstruction † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Stomatitis † 1	0/259 (0.00%)	0	4/25 (16.00%)	4	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vomiting † 1	5/259 (1.93%)	6	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
General disorders
Asthenia † 1	4/259 (1.54%)	4	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Chest pain † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Death † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Fatigue † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastrointestinal complication associated with device † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Influenza like illness † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Multiple organ dysfunction syndrome † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Non-cardiac chest pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pyrexia † 1	3/259 (1.16%)	3	1/25 (4.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Systemic inflammatory response syndrome † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatobiliary disorders
Bile duct stenosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Biliary obstruction † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cholangitis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cholecystitis acute † 1	1/259 (0.39%)	1	1/25 (4.00%)	1	1/31 (3.23%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatic failure † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatic function abnormal † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatic haematoma † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatic pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hepatitis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Jaundice † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Portal vein thrombosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Infections and infestations
Abdominal abscess † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Bacteraemia † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Clostridium difficile infection † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Disseminated varicella zoster virus infection † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Diverticulitis intestinal haemorrhagic † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Encephalitis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Liver abscess † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Osteomyelitis † 1	1/259 (0.39%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pharyngitis † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumocystis jirovecii pneumonia † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumonia † 1	4/259 (1.54%)	6	0/25 (0.00%)	0	2/31 (6.45%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pyelonephritis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Sepsis † 1	5/259 (1.93%)	5	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Septic shock † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Staphylococcal bacteraemia † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Subdiaphragmatic abscess † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Urinary tract infection † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Wound infection † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Injury, poisoning and procedural complications
Anastomotic stenosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Post procedural haemorrhage † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Rib fracture † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Thoracic vertebral fracture † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vascular pseudoaneurysm † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Aspartate aminotransferase increased † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Blood bilirubin increased † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Blood creatine phosphokinase increased † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Blood creatinine increased † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Transaminases increased † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Urine output decreased † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	1/259 (0.39%)	1	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dehydration † 1	4/259 (1.54%)	4	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Failure to thrive † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypercalcaemia † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hyperglycaemia † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hyponatraemia † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Back pain † 1	5/259 (1.93%)	5	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Musculoskeletal chest pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Musculoskeletal pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Myositis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Neck pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pain in extremity † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Polymyalgia rheumatica † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Metastases to adrenals † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oesophageal squamous cell carcinoma † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Renal cancer † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Squamous cell carcinoma of skin † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Tumour pain † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Nervous system disorders
Altered state of consciousness † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cauda equina syndrome † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Cerebrovascular accident † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dizziness † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dysarthria † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Seizure † 1	1/259 (0.39%)	1	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Syncope † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Transient ischaemic attack † 1	1/259 (0.39%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Unresponsive to stimuli † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vertebral artery occlusion † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Psychiatric disorders
Anxiety † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Confusional state † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Delirium † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Depression † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Drug dependence † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	6/259 (2.32%)	6	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Chronic kidney disease † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hydronephrosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Nephrotic syndrome † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypoxia † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pleural effusion † 1	9/259 (3.47%)	9	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumonia aspiration † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumonitis † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pulmonary embolism † 1	6/259 (2.32%)	6	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Respiratory failure † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Skin and subcutaneous tissue disorders
Lichen planus † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome † 1	0/259 (0.00%)	0	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Rash maculo-papular † 1	0/259 (0.00%)	0	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Embolism † 1	1/259 (0.39%)	1	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Haematoma † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Internal haemorrhage † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vena cava thrombosis † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cohort 1 First Course		Cohort 2 First Course		Cohort 3 First Course		Cohort 1 Second Course		Cohort 2 Second Course		Cohort 3 Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	237/259 (91.51%)		25/25 (100.00%)		31/31 (100.00%)		0/3 (0.00%)		0/1 (0.00%)		0/2 (0.00%)
Blood and lymphatic system disorders
Anaemia † 1	58/259 (22.39%)	69	11/25 (44.00%)	13	7/31 (22.58%)	9	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Leukopenia † 1	4/259 (1.54%)	7	2/25 (8.00%)	3	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Neutropenia † 1	3/259 (1.16%)	3	9/25 (36.00%)	12	1/31 (3.23%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Thrombocytopenia † 1	8/259 (3.09%)	10	3/25 (12.00%)	5	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Ear and labyrinth disorders
Tinnitus † 1	0/259 (0.00%)	0	4/25 (16.00%)	4	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Endocrine disorders
Hyperthyroidism † 1	10/259 (3.86%)	10	4/25 (16.00%)	4	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypothyroidism † 1	24/259 (9.27%)	24	2/25 (8.00%)	2	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastrointestinal disorders
Abdominal discomfort † 1	2/259 (0.77%)	2	2/25 (8.00%)	2	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Abdominal distension † 1	15/259 (5.79%)	15	2/25 (8.00%)	2	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Abdominal pain † 1	49/259 (18.92%)	56	3/25 (12.00%)	3	8/31 (25.81%)	13	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Abdominal pain upper † 1	19/259 (7.34%)	25	4/25 (16.00%)	8	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Ascites † 1	16/259 (6.18%)	18	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Constipation † 1	52/259 (20.08%)	57	14/25 (56.00%)	22	7/31 (22.58%)	7	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Diarrhoea † 1	46/259 (17.76%)	55	14/25 (56.00%)	18	8/31 (25.81%)	13	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dry mouth † 1	8/259 (3.09%)	8	2/25 (8.00%)	4	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dyspepsia † 1	9/259 (3.47%)	9	2/25 (8.00%)	3	3/31 (9.68%)	4	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dysphagia † 1	31/259 (11.97%)	36	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gastrooesophageal reflux disease † 1	10/259 (3.86%)	12	2/25 (8.00%)	4	2/31 (6.45%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Nausea † 1	65/259 (25.10%)	74	15/25 (60.00%)	22	8/31 (25.81%)	10	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Stomatitis † 1	10/259 (3.86%)	10	17/25 (68.00%)	29	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vomiting † 1	36/259 (13.90%)	44	10/25 (40.00%)	23	6/31 (19.35%)	12	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
General disorders
Asthenia † 1	24/259 (9.27%)	26	4/25 (16.00%)	7	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Chest discomfort † 1	2/259 (0.77%)	2	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Fatigue † 1	93/259 (35.91%)	105	10/25 (40.00%)	13	10/31 (32.26%)	10	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Generalised oedema † 1	0/259 (0.00%)	0	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Influenza like illness † 1	4/259 (1.54%)	5	0/25 (0.00%)	0	4/31 (12.90%)	5	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Malaise † 1	7/259 (2.70%)	7	5/25 (20.00%)	14	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Mucosal inflammation † 1	1/259 (0.39%)	1	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oedema † 1	9/259 (3.47%)	9	4/25 (16.00%)	10	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oedema peripheral † 1	43/259 (16.60%)	57	1/25 (4.00%)	1	4/31 (12.90%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pyrexia † 1	25/259 (9.65%)	35	6/25 (24.00%)	9	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Infections and infestations
Nasopharyngitis † 1	7/259 (2.70%)	8	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumonia † 1	8/259 (3.09%)	10	2/25 (8.00%)	3	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	14/259 (5.41%)	19	2/25 (8.00%)	3	2/31 (6.45%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Aspartate aminotransferase increased † 1	30/259 (11.58%)	34	2/25 (8.00%)	2	4/31 (12.90%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Blood alkaline phosphatase increased † 1	31/259 (11.97%)	32	1/25 (4.00%)	1	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Blood creatinine increased † 1	13/259 (5.02%)	15	5/25 (20.00%)	6	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Gamma-glutamyltransferase increased † 1	7/259 (2.70%)	9	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Haemoglobin decreased † 1	4/259 (1.54%)	4	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Lymphocyte count decreased † 1	6/259 (2.32%)	8	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Neutrophil count decreased † 1	2/259 (0.77%)	3	13/25 (52.00%)	30	1/31 (3.23%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Platelet count decreased † 1	3/259 (1.16%)	4	5/25 (20.00%)	7	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Weight decreased † 1	38/259 (14.67%)	41	5/25 (20.00%)	6	4/31 (12.90%)	4	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Weight increased † 1	2/259 (0.77%)	2	3/25 (12.00%)	13	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
White blood cell count decreased † 1	2/259 (0.77%)	2	4/25 (16.00%)	9	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	73/259 (28.19%)	81	13/25 (52.00%)	22	11/31 (35.48%)	14	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dehydration † 1	15/259 (5.79%)	20	2/25 (8.00%)	2	2/31 (6.45%)	4	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Diabetes mellitus † 1	0/259 (0.00%)	0	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hyperglycaemia † 1	23/259 (8.88%)	29	3/25 (12.00%)	6	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypoalbuminaemia † 1	24/259 (9.27%)	24	1/25 (4.00%)	1	4/31 (12.90%)	4	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypokalaemia † 1	12/259 (4.63%)	13	3/25 (12.00%)	3	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypomagnesaemia † 1	2/259 (0.77%)	2	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hyponatraemia † 1	23/259 (8.88%)	26	1/25 (4.00%)	2	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypophosphataemia † 1	10/259 (3.86%)	14	2/25 (8.00%)	4	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	36/259 (13.90%)	58	3/25 (12.00%)	3	5/31 (16.13%)	8	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Back pain † 1	34/259 (13.13%)	38	2/25 (8.00%)	2	6/31 (19.35%)	7	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Flank pain † 1	5/259 (1.93%)	5	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Groin pain † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Muscular weakness † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Myalgia † 1	8/259 (3.09%)	10	2/25 (8.00%)	2	5/31 (16.13%)	7	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pain in extremity † 1	9/259 (3.47%)	12	0/25 (0.00%)	0	5/31 (16.13%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Nervous system disorders
Dizziness † 1	17/259 (6.56%)	17	4/25 (16.00%)	5	4/31 (12.90%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dysgeusia † 1	6/259 (2.32%)	6	6/25 (24.00%)	9	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Headache † 1	12/259 (4.63%)	13	5/25 (20.00%)	5	3/31 (9.68%)	6	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Neuropathy peripheral † 1	3/259 (1.16%)	3	3/25 (12.00%)	3	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Peripheral sensory neuropathy † 1	5/259 (1.93%)	5	6/25 (24.00%)	7	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Syncope † 1	2/259 (0.77%)	3	2/25 (8.00%)	3	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Psychiatric disorders
Anxiety † 1	15/259 (5.79%)	18	0/25 (0.00%)	0	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Insomnia † 1	17/259 (6.56%)	20	9/25 (36.00%)	9	2/31 (6.45%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	44/259 (16.99%)	50	2/25 (8.00%)	2	6/31 (19.35%)	8	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dyspnoea † 1	40/259 (15.44%)	43	1/25 (4.00%)	2	5/31 (16.13%)	7	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Epistaxis † 1	3/259 (1.16%)	3	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hiccups † 1	4/259 (1.54%)	4	8/25 (32.00%)	16	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Oropharyngeal pain † 1	8/259 (3.09%)	8	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pleural effusion † 1	11/259 (4.25%)	14	2/25 (8.00%)	2	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pneumonitis † 1	2/259 (0.77%)	2	1/25 (4.00%)	1	3/31 (9.68%)	4	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	3/259 (1.16%)	3	4/25 (16.00%)	4	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Dry skin † 1	17/259 (6.56%)	18	2/25 (8.00%)	2	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome † 1	1/259 (0.39%)	1	3/25 (12.00%)	3	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Pruritus † 1	33/259 (12.74%)	39	4/25 (16.00%)	7	8/31 (25.81%)	10	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Rash † 1	31/259 (11.97%)	33	2/25 (8.00%)	2	3/31 (9.68%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Rash maculo-papular † 1	5/259 (1.93%)	5	1/25 (4.00%)	1	2/31 (6.45%)	3	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Skin hyperpigmentation † 1	1/259 (0.39%)	1	2/25 (8.00%)	2	1/31 (3.23%)	1	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Skin lesion † 1	3/259 (1.16%)	3	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Urticaria † 1	1/259 (0.39%)	1	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vascular disorders
Hypertension † 1	14/259 (5.41%)	20	1/25 (4.00%)	1	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Hypotension † 1	10/259 (3.86%)	12	0/25 (0.00%)	0	2/31 (6.45%)	2	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
Vasculitis † 1	0/259 (0.00%)	0	2/25 (8.00%)	2	0/31 (0.00%)	0	0/3 (0.00%)	0	0/1 (0.00%)	0	0/2 (0.00%)	0
1 Term from vocabulary, MedDRA 24.0; † 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 trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.

Results Point of Contact

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

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

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.

Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, Bang YJ, De Vita F, Landers G, Yen CJ, Chau I, Elme A, Lee J, Ozguroglu M, Catenacci D, Yoon HH, Chen E, Adelberg D, Shih CS, Shah S, Bhagia P, Wainberg ZA. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. JAMA Oncol. 2021 Jun 1;7(6):895-902. doi: 10.1001/jamaoncol.2021.0275.

Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, Hara H, Golan T, Garrido M, Jalal SI, Borg C, Doi T, Yoon HH, Savage MJ, Wang J, Dalal RP, Shah S, Wainberg ZA, Chung HC. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019 Jul;22(4):828-837. doi: 10.1007/s10120-018-00909-5. Epub 2019 Mar 25.

Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 May 10;4(5):e180013. doi: 10.1001/jamaoncol.2018.0013. Epub 2018 May 10. Erratum In: JAMA Oncol. 2019 Apr 1;5(4):579.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02335411
• Other Study ID Numbers: 3475-059; MK-3475-059 ( Other Identifier: Merck ); KEYNOTE-059 ( Other Identifier: Merck ); 2014-003574-16 ( EudraCT Number )
• First Submitted: January 7, 2015
• First Posted: January 9, 2015
• Results First Submitted: July 13, 2022
• Results First Posted: August 8, 2022
• Last Update Posted: August 8, 2022