Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

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ClinicalTrials.gov Identifier: NCT01704287

Recruitment Status : Completed

First Posted : October 11, 2012

Results First Posted : March 28, 2017

Last Update Posted : May 18, 2020

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Sponsor:

Information provided by (Responsible Party):

Merck Sharp & Dohme LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Malignant Melanoma
Interventions	Biological: Pembrolizumab Drug: Carboplatin Drug: Paclitaxel Drug: Dacarbazine Drug: Temozolomide
Enrollment	540

Participant Flow

Recruitment Details
Pre-assignment Details	This end of trial analysis is based on a trial closure database cutoff date of 31-Jan-2019.


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg
Arm/Group Description	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...	Participants who were initially ran...	Participants who were initially ran...
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Period Title: Initial Treatment Period
Started	180	181	179	0	0
Treated	178	179	171	0	0
Completed	33	47	6	0	0
Not Completed	147	134	173	0	0
Reason Not Completed
Death	139	129	71	0	0
Withdrawal by Subject	3	2	4	0	0
Lost to Follow-up	5	3	0	0	0
Switched to Pembrolizumab	0	0	98	0	0
Period Title: Switch to Pembrolizumab Treatment Period
Started	0	0	0	53	45
Completed	0	0	0	15	7
Not Completed	0	0	0	38	38
Reason Not Completed
Lost to Follow-up	0	0	0	2	1
Death	0	0	0	35	37
Withdrawal by Subject	0	0	0	1	0

Baseline Characteristics

Arm/Group Title		Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)	Total
Arm/Group Description		Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...	Total of all reporting groups
Arm/Group Description		Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Total of all reporting groups
Overall Number of Baseline Participants		180	181	179	540
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The baseline analysis population consisted of all randomized participants. Participants were included in the group to which they were initially randomized for Baseline Characteristics.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	180 participants	181 participants	179 participants	540 participants
		59.5 (14.9)	60.1 (13.3)	60.5 (12.7)	60.1 (13.6)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	180 participants	181 participants	179 participants	540 participants
	Female	76 42.2%	72 39.8%	65 36.3%	213 39.4%
	Male	104 57.8%	109 60.2%	114 63.7%	327 60.6%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	180 participants	181 participants	179 participants	540 participants
	PD-L1 Positive	99 55.0%	97 53.6%	98 54.7%	294 54.4%
	PD-L1 Negative	48 26.7%	46 25.4%	40 22.3%	134 24.8%
	Unknown	33 18.3%	38 21.0%	41 22.9%	112 20.7%
		[1] Measure Description: Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by immunohistochemistry assay and scored on a unique melanoma (Allred Proportion Score [APS]/Melanoma [MEL]) scale of 0 to 5 points. Participants with an APS score of ≥2 (membranous staining in ≥1% of cells) were considered to be PD-L1 Positive and participants with an APS score of 0 or 1 were considered to be PD-L1 Negative.

Outcome Measures

1.Primary Outcome


Title	Progression-free Survival (PFS) - Initial Treatment Period
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 Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD 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 have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	180	181	179
Median (95% Confidence Interval) Unit of Measure: Months
	2.9 (2.8 to 3.8)	3.0 (2.8 to 5.2)	2.8 (2.6 to 2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); lactate dehydrogenase (LDH) levels (normal vs. elevated LDH levels [≥110% Upper Limit of Normal (ULN)]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	P-Value	<0.0001
	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	0.58
	Confidence Interval	(2-Sided) 95% 0.46 to 0.73
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	P-Value	<0.0001
	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	0.47
	Confidence Interval	(2-Sided) 95% 0.37 to 0.60
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	P-Value	0.1247
	Comments	Two-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	0.83
	Confidence Interval	(2-Sided) 95% 0.66 to 1.05
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

2.Primary Outcome


Title	Interim Overall Survival (OS) - Initial Treatment Period
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. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	180	181	179
Median (95% Confidence Interval) Unit of Measure: Months
	13.4 (11.0 to 16.4)	14.7 (11.3 to 19.5)	11.0 (8.9 to 13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1173
	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	0.86
	Confidence Interval	(2-Sided) 95% 0.67 to 1.10
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0106
	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	0.74
	Confidence Interval	(2-Sided) 95% 0.57 to 0.96
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2905
	Comments	Two-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	0.87
	Confidence Interval	(2-Sided) 95% 0.67 to 1.12
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

3.Primary Outcome


Title	Final Overall Survival (OS) - Initial Treatment Period
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. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	180	181	179
Median (95% Confidence Interval) Unit of Measure: Months
	13.4 (11.0 to 16.4)	14.7 (11.3 to 19.5)	11.0 (8.9 to 13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1146
	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	0.86
	Confidence Interval	(2-Sided) 95% 0.68 to 1.10
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0023
	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	0.71
	Confidence Interval	(2-Sided) 95% 0.55 to 0.90
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1490
	Comments	Two-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	0.84
	Confidence Interval	(2-Sided) 95% 0.66 to 1.07
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

4.Secondary Outcome


Title	Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
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. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.


Arm/Group Title		Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:		Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:		Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed		180	181	179
Median (95% Confidence Interval) Unit of Measure: Months
PD-L1 Positive	Number Analyzed	99 participants	97 participants	98 participants
PD-L1 Positive		15.0 (10.9 to 20.9)	17.5 (13.7 to 28.9)	12.1 (7.7 to 18.2)
PD-L1 Negative	Number Analyzed	48 participants	46 participants	40 participants
PD-L1 Negative		10.5 (6.4 to 13.5)	13.4 (4.6 to 23.3)	9.3 (5.1 to 14.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1-Positive Participants

Statistical Test of Hypothesis	P-Value	0.3113
	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% 0.66 to 1.28
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Positive Participants

Statistical Test of Hypothesis	P-Value	0.0208
	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% 0.50 to 0.99
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Positive Participants

Statistical Test of Hypothesis	P-Value	0.0496
	Comments	Two-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	0.71
	Confidence Interval	(2-Sided) 95% 0.50 to 1.00
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	P-Value	0.6043
	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	1.07
	Confidence Interval	(2-Sided) 95% 0.65 to 1.76
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	P-Value	0.0335
	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	0.62
	Confidence Interval	(2-Sided) 95% 0.37 to 1.04
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	P-Value	0.1504
	Comments	Two-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	0.71
	Confidence Interval	(2-Sided) 95% 0.44 to 1.13
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

5.Secondary Outcome


Title	Overall Response Rate (ORR) - Initial Treatment Period
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: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	180	181	179
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	22.2 (16.4 to 29.0)	27.6 (21.3 to 34.7)	4.5 (1.9 to 8.6)

6.Secondary Outcome


Title	Best Overall Response (BOR) - Initial Treatment Period
Description	BOR was assessed by independent radiology review using RECIST 1.1 and ...
Description	BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	180	181	179
Measure Type: Number Unit of Measure: Percentage of Participants
Complete Response	3.3	7.2	0.0
Partial Response	18.9	20.4	4.5
Stable Disease	16.7	14.9	19.0
Progressive Disease	46.7	47.5	61.5
Not Evaluable	13.3	9.9	15.1
No Disease	0.6	0.0	0.0
No Assessment	0.6	0.0	0.0

7.Secondary Outcome


Title	Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
Description	The BOR was assessed using RECIST 1.1 and was recorded from the start ...
Description	The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants in ICC who switched to receiving pembrolizumab. Participants were included in the treatment group to which they were re-randomized (switched) for this efficacy analysis.


Arm/Group Title	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg
Arm/Group Description:	Participants who were initially ran...	Participants who were initially ran...
Arm/Group Description:	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	53	45
Measure Type: Number Unit of Measure: Percentage of Participants
Complete Response	1.9	4.4
Partial Response	17.0	13.3
Stable Disease	15.1	11.1
Progressive Disease	54.7	55.6
Not Evaluable	11.3	13.3
No Assessment	0.0	2.2

8.Secondary Outcome


Title	Duration of Response (DOR) - Initial Treatment Period
Description	For participants who demonstrated a confirmed response (Complete Respo...
Description	For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were initially randomi...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	40	50	8
Median (Full Range) Unit of Measure: Months
	22.8 (1.4 to 25.3)	NA ^[1] (1.1 to NA)	6.8 (2.8 to 11.3)

[1]

NA=DOR Median not reached NA=DOR Upper Limit not reached: no progressive disease by time of last assessment

9.Secondary Outcome


Title	Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
Description	An AE was defined as any unfavorable and unintended change in the stru...
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants who received at least one dose of study drug.


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	ICC Only	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg	ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)	ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were randomized to rec...	Participants who were initially ran...	Participants who were initially ran...	Participants who were initially ran...	Participants who were initially ran...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	178	179	73	53	45	53	45
Measure Type: Count of Participants Unit of Measure: Participants
	172 96.6%	179 100.0%	71 97.3%	52 98.1%	45 100.0%	53 100.0%	41 91.1%

10.Secondary Outcome


Title	Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
Description	An AE was defined as any unfavorable and unintended change in the stru...
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants who received at least one dose of study drug.


Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	ICC Only	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg	ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)	ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description:	Participants were initially randomi...	Participants were initially randomi...	Participants were randomized to rec...	Participants who were initially ran...	Participants who were initially ran...	Participants who were initially ran...	Participants who were initially ran...
Arm/Group Description:	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed	178	179	73	53	45	53	45
Measure Type: Count of Participants Unit of Measure: Participants
	29 16.3%	33 18.4%	13 17.8%	1 1.9%	1 2.2%	4 7.5%	4 8.9%

Adverse Events

Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Adverse Event Reporting Description	Safety Population: All participants who received ≥1 dose of study drug. Per protocol, disease progression of cancer under study was not considered an AE unless considered related to study drug. Therefore, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Arm/Group Title	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description	Participants received 1 of 4 possib...		Participants who were initially ran...		Participants who were initially ran...		Participants were initially randomi...		Participants were initially randomi...		Participants who were initially ran...		Participants who were initiall rand...
Arm/Group Description	Participants received 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the final analysis. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants who were initiall randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
All-Cause Mortality
	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	71/73 (97.26%)		0/53 (0.00%)		0/45 (0.00%)		139/178 (78.09%)		129/179 (72.07%)		35/53 (66.04%)		37/45 (82.22%)
Serious Adverse Events Serious Adverse Events
	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
	Affected / at Risk (%)	# Events	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	33/73 (45.21%)		15/53 (28.30%)		9/45 (20.00%)		91/178 (51.12%)		78/179 (43.58%)		18/53 (33.96%)		18/45 (40.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	3/73 (4.11%)	3	1/53 (1.89%)	1	0/45 (0.00%)	0	7/178 (3.93%)	7	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Febrile neutropenia ^† 1	2/73 (2.74%)	2	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Leukopenia ^† 1	1/73 (1.37%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Neutropenia ^† 1	1/73 (1.37%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Thrombocytopenia ^† 1	2/73 (2.74%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Cardiac disorders
Atrial fibrillation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Atrioventricular block complete ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Cardiac failure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cardiac ventricular disorder ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cardiogenic shock ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Myocardial infarction ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Pericardial effusion ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Ear and labyrinth disorders
Vertigo positional ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Endocrine disorders
Adrenal insufficiency ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Addison's disease ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Adrenocortical insufficiency acute ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hyperparathyroidism ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypophysitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypopituitarism ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Secondary adrenocortical insufficiency ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Inappropriate antidiuretic hormone secretion ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Eye disorders
Eye movement disorder ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Iritis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastrointestinal disorders
Colitis ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1
Diarrhoea ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	1/178 (0.56%)	1	4/179 (2.23%)	4	1/53 (1.89%)	1	1/45 (2.22%)	1
Dysphagia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Pancreatitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	2	1/53 (1.89%)	1	0/45 (0.00%)	0
Rectal haemorrhage ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Small intestinal obstruction ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1
Abdominal pain ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	4/179 (2.23%)	4	0/53 (0.00%)	0	0/45 (0.00%)	0
Ascites ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Autoimmune colitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Constipation ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Diverticular perforation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Diverticulum ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastric disorder ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastrointestinal disorder ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastrointestinal pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Haematemesis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Haematochezia ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Ileus ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Intestinal obstruction ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Intussusception ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Large intestinal ulcer ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Large intestine perforation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Malabsorption ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Nausea ^† 1	3/73 (4.11%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Small intestinal perforation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Upper gastrointestinal haemorrhage ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Vomiting ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastritis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Lower gastrointestinal haemorrhage ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	2/45 (4.44%)	2
Gastrointestinal haemorrhage ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
General disorders
Generalised oedema ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	3/178 (1.69%)	3	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Asthenia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Chest pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Cyst ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Death ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Fatigue ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Gait disturbance ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
General physical health deterioration ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	6/179 (3.35%)	6	0/53 (0.00%)	0	0/45 (0.00%)	0
Infusion site extravasation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Malaise ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Oedema ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Pyrexia ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1	3/178 (1.69%)	4	4/179 (2.23%)	5	0/53 (0.00%)	0	0/45 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cholangitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cholecystitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	3/178 (1.69%)	3	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hepatic failure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hepatic necrosis ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hyperbilirubinaemia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Bile duct obstruction ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Immune system disorders
Anaphylactic reaction ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypersensitivity ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cytokine release syndrome ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Infections and infestations
Clostridium difficile colitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Diverticulitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Pneumonia ^† 1	3/73 (4.11%)	3	0/53 (0.00%)	0	2/45 (4.44%)	2	2/178 (1.12%)	2	3/179 (1.68%)	5	3/53 (5.66%)	3	1/45 (2.22%)	1
Sepsis ^† 1	2/73 (2.74%)	2	1/53 (1.89%)	1	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1
Wound infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Appendicitis perforated ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Bacteraemia ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Bronchitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Candida infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cellulitis ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Cellulitis streptococcal ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Enterocolitis infectious ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Erysipelas ^† 1	1/73 (1.37%)	1	1/53 (1.89%)	1	0/45 (0.00%)	0	2/178 (1.12%)	2	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Gastroenteritis viral ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Herpes zoster ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Infected cyst ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Infection ^† 1	2/73 (2.74%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Infectious pleural effusion ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Influenza ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Mastitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Osteomyelitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Pelvic abscess ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Respiratory syncytial virus infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Salmonellosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Septic shock ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Skin infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Soft tissue infection ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Streptococcal sepsis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Urinary tract infection ^† 1	2/73 (2.74%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Viral infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Viral rash ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Viral upper respiratory tract infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Abdominal abscess ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Lung infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Postoperative wound infection ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Urosepsis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Injury, poisoning and procedural complications
Fall ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Femur fracture ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Fracture displacement ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hip fracture ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Limb injury ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Lower limb fracture ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Radiation necrosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Rib fracture ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Spinal fracture ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Traumatic intracranial haemorrhage ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Accidental overdose ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Aspartate aminotransferase increased ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hepatic enzyme increased ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Neutrophil count decreased ^† 1	1/73 (1.37%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Platelet count decreased ^† 1	2/73 (2.74%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
White blood cell count decreased ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Metabolism and nutrition disorders
Cachexia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Dehydration ^† 1	1/73 (1.37%)	1	1/53 (1.89%)	1	0/45 (0.00%)	0	4/178 (2.25%)	4	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Diabetic metabolic decompensation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypercalcaemia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypocalcaemia ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hyponatraemia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	3/179 (1.68%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Hyperglycaemia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Type 1 diabetes mellitus ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	2/179 (1.12%)	2	0/53 (0.00%)	0	1/45 (2.22%)	1
Pain in extremity ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Back pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Groin pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Musculoskeletal pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Neck pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Osteoarthritis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Osteolysis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Spondylolisthesis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cervical spine stenosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Metastases to central nervous system ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	3/178 (1.69%)	3	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Tumour pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	1/178 (0.56%)	1	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Basal cell carcinoma ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	3	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cancer pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Colon cancer metastatic ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Intestinal metastasis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Invasive ductal breast carcinoma ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Metastases to lymph nodes ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Metastases to meninges ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Metastasis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Oncologic complication ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Prostate cancer ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Rectal cancer ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Small cell carcinoma ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Squamous cell carcinoma ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Squamous cell carcinoma of skin ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Tumour haemorrhage ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	1/53 (1.89%)	1	0/45 (0.00%)	0
Hemiparesis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1
Seizure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	1/53 (1.89%)	1	2/45 (4.44%)	2
Syncope ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Aphasia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Ataxia ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Brain oedema ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Cerebrovascular accident ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Encephalopathy ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Epilepsy ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Haemorrhage intracranial ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hemiplegia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Lumbar radiculopathy ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Meningitis noninfective ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Myasthenic syndrome ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Myoclonus ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Neuropathy peripheral ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Paraesthesia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Partial seizures ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Presyncope ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Sciatica ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Spinal cord compression ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Transient ischaemic attack ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Peripheral motor neuropathy ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Product Issues
Device dislocation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Psychiatric disorders
Confusional state ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	2/178 (1.12%)	2	3/179 (1.68%)	3	1/53 (1.89%)	1	0/45 (0.00%)	0
Delirium ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Mental status changes ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Hydronephrosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Postrenal failure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Renal failure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Tubulointerstitial nephritis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Urinary tract obstruction ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Renal impairment ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Reproductive system and breast disorders
Pelvic pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	2/178 (1.12%)	2	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Dyspnoea ^† 1	3/73 (4.11%)	3	0/53 (0.00%)	0	1/45 (2.22%)	1	2/178 (1.12%)	2	5/179 (2.79%)	5	1/53 (1.89%)	1	0/45 (0.00%)	0
Pleural effusion ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	1/45 (2.22%)	1
Pulmonary embolism ^† 1	2/73 (2.74%)	2	2/53 (3.77%)	2	0/45 (0.00%)	0	2/178 (1.12%)	2	1/179 (0.56%)	1	1/53 (1.89%)	1	0/45 (0.00%)	0
Cough ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Dyspnoea exertional ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Epistaxis ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Haemoptysis ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	2	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypoxia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Interstitial lung disease ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)
Laryngeal inflammation ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Pneumonia aspiration ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Pneumonitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	3/179 (1.68%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Pneumothorax ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Pulmonary thrombosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Acute respiratory failure ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Alveolitis allergic ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Skin and subcutaneous tissue disorders
Lichenoid keratosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Rash maculo-papular ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Skin mass ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Stevens-Johnson syndrome ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Purpura ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
Vascular disorders
Hypotension ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0
Circulatory collapse ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Deep vein thrombosis ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	0/45 (0.00%)	0	1/178 (0.56%)	1	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Lymphoedema ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Orthostatic hypotension ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Phlebitis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Poor venous access ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	1/178 (0.56%)	1	0/179 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0
Venous thrombosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	1/179 (0.56%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0
Thrombosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1
1 Term from vocabulary, MedDRA 21.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
	Affected / at Risk (%)	# Events	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	66/73 (90.41%)		52/53 (98.11%)		44/45 (97.78%)		158/178 (88.76%)		176/179 (98.32%)		48/53 (90.57%)		36/45 (80.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	21/73 (28.77%)	26	15/53 (28.30%)	25	10/45 (22.22%)	10	30/178 (16.85%)	43	26/179 (14.53%)	31	12/53 (22.64%)	13	8/45 (17.78%)	21
Leukopenia ^† 1	8/73 (10.96%)	8	3/53 (5.66%)	6	4/45 (8.89%)	7	0/178 (0.00%)	0	2/179 (1.12%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Neutropenia ^† 1	2/73 (2.74%)	2	7/53 (13.21%)	14	5/45 (11.11%)	8	1/178 (0.56%)	1	2/179 (1.12%)	4	0/53 (0.00%)	0	0/45 (0.00%)	0
Thrombocytopenia ^† 1	9/73 (12.33%)	12	7/53 (13.21%)	10	2/45 (4.44%)	2	3/178 (1.69%)	5	3/179 (1.68%)	5	0/53 (0.00%)	0	0/45 (0.00%)	0
Cardiac disorders
Tachycardia ^† 1	4/73 (5.48%)	4	2/53 (3.77%)	3	0/45 (0.00%)	0	3/178 (1.69%)	4	7/179 (3.91%)	7	0/53 (0.00%)	0	0/45 (0.00%)	0
Ear and labyrinth disorders
Vertigo ^† 1	3/73 (4.11%)	3	1/53 (1.89%)	1	0/45 (0.00%)	0	4/178 (2.25%)	8	10/179 (5.59%)	11	0/53 (0.00%)	0	0/45 (0.00%)	0
Endocrine disorders
Hypothyroidism ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	1/45 (2.22%)	1	16/178 (8.99%)	17	15/179 (8.38%)	16	4/53 (7.55%)	4	3/45 (6.67%)	3
Eye disorders
Dry eye ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	3	0/45 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	8/73 (10.96%)	10	1/53 (1.89%)	2	4/45 (8.89%)	4	28/178 (15.73%)	38	27/179 (15.08%)	33	7/53 (13.21%)	7	2/45 (4.44%)	3
Constipation ^† 1	16/73 (21.92%)	19	12/53 (22.64%)	17	8/45 (17.78%)	10	40/178 (22.47%)	47	42/179 (23.46%)	57	12/53 (22.64%)	14	6/45 (13.33%)	6
Diarrhoea ^† 1	13/73 (17.81%)	20	11/53 (20.75%)	17	11/45 (24.44%)	17	40/178 (22.47%)	52	41/179 (22.91%)	67	16/53 (30.19%)	23	9/45 (20.00%)	22
Dyspepsia ^† 1	2/73 (2.74%)	2	2/53 (3.77%)	3	3/45 (6.67%)	3	3/178 (1.69%)	3	4/179 (2.23%)	5	4/53 (7.55%)	4	2/45 (4.44%)	2
Nausea ^† 1	23/73 (31.51%)	30	29/53 (54.72%)	44	19/45 (42.22%)	23	44/178 (24.72%)	74	49/179 (27.37%)	56	12/53 (22.64%)	12	10/45 (22.22%)	17
Vomiting ^† 1	17/73 (23.29%)	22	10/53 (18.87%)	14	13/45 (28.89%)	14	19/178 (10.67%)	26	38/179 (21.23%)	58	6/53 (11.32%)	7	2/45 (4.44%)	2
Abdominal distension ^† 1	1/73 (1.37%)	1	3/53 (5.66%)	3	0/45 (0.00%)	0	11/178 (6.18%)	13	9/179 (5.03%)	10	0/53 (0.00%)	0	0/45 (0.00%)	0
Abdominal pain upper ^† 1	2/73 (2.74%)	2	0/53 (0.00%)	0	2/45 (4.44%)	2	6/178 (3.37%)	6	12/179 (6.70%)	12	0/53 (0.00%)	0	0/45 (0.00%)	0
Dry mouth ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	9/178 (5.06%)	11	7/179 (3.91%)	10	0/53 (0.00%)	0	0/45 (0.00%)	0
Dysphagia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	4	0/45 (0.00%)	0
General disorders
Asthenia ^† 1	10/73 (13.70%)	11	4/53 (7.55%)	4	2/45 (4.44%)	2	19/178 (10.67%)	25	20/179 (11.17%)	44	2/53 (3.77%)	2	3/45 (6.67%)	3
Fatigue ^† 1	28/73 (38.36%)	34	27/53 (50.94%)	36	26/45 (57.78%)	33	74/178 (41.57%)	106	91/179 (50.84%)	117	15/53 (28.30%)	17	16/45 (35.56%)	24
Influenza like illness ^† 1	1/73 (1.37%)	2	1/53 (1.89%)	1	1/45 (2.22%)	1	9/178 (5.06%)	13	14/179 (7.82%)	17	4/53 (7.55%)	4	3/45 (6.67%)	6
Oedema peripheral ^† 1	4/73 (5.48%)	4	5/53 (9.43%)	5	1/45 (2.22%)	1	17/178 (9.55%)	19	21/179 (11.73%)	24	6/53 (11.32%)	7	2/45 (4.44%)	2
Pain ^† 1	0/73 (0.00%)	0	4/53 (7.55%)	5	1/45 (2.22%)	1	6/178 (3.37%)	7	7/179 (3.91%)	7	3/53 (5.66%)	3	0/45 (0.00%)	0
Pyrexia ^† 1	7/73 (9.59%)	7	5/53 (9.43%)	7	5/45 (11.11%)	6	23/178 (12.92%)	33	30/179 (16.76%)	43	3/53 (5.66%)	4	8/45 (17.78%)	8
Chest pain ^† 1	3/73 (4.11%)	3	3/53 (5.66%)	4	1/45 (2.22%)	1	7/178 (3.93%)	8	11/179 (6.15%)	15	0/53 (0.00%)	0	0/45 (0.00%)	0
Chills ^† 1	0/73 (0.00%)	0	3/53 (5.66%)	3	5/45 (11.11%)	5	10/178 (5.62%)	11	11/179 (6.15%)	13	0/53 (0.00%)	0	0/45 (0.00%)	0
Malaise ^† 1	0/73 (0.00%)	0	3/53 (5.66%)	3	0/45 (0.00%)	0	7/178 (3.93%)	9	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Infections and infestations
Nasopharyngitis ^† 1	2/73 (2.74%)	2	4/53 (7.55%)	4	1/45 (2.22%)	1	10/178 (5.62%)	11	20/179 (11.17%)	36	4/53 (7.55%)	9	0/45 (0.00%)	0
Upper respiratory tract infection ^† 1	1/73 (1.37%)	1	1/53 (1.89%)	2	2/45 (4.44%)	2	8/178 (4.49%)	12	18/179 (10.06%)	25	5/53 (9.43%)	6	3/45 (6.67%)	3
Urinary tract infection ^† 1	5/73 (6.85%)	5	2/53 (3.77%)	2	2/45 (4.44%)	2	17/178 (9.55%)	19	17/179 (9.50%)	23	8/53 (15.09%)	8	2/45 (4.44%)	2
Oral herpes ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	3	1/45 (2.22%)	1
Investigations
Alanine aminotransferase increased ^† 1	0/73 (0.00%)	0	2/53 (3.77%)	2	3/45 (6.67%)	4	9/178 (5.06%)	10	13/179 (7.26%)	18	3/53 (5.66%)	4	2/45 (4.44%)	4
Aspartate aminotransferase increased ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	2	1/45 (2.22%)	1	11/178 (6.18%)	11	14/179 (7.82%)	17	3/53 (5.66%)	4	1/45 (2.22%)	1
Blood alkaline phosphatase increased ^† 1	2/73 (2.74%)	2	1/53 (1.89%)	1	2/45 (4.44%)	2	12/178 (6.74%)	13	10/179 (5.59%)	16	4/53 (7.55%)	4	2/45 (4.44%)	2
Weight decreased ^† 1	1/73 (1.37%)	1	4/53 (7.55%)	5	3/45 (6.67%)	3	12/178 (6.74%)	12	17/179 (9.50%)	17	4/53 (7.55%)	5	1/45 (2.22%)	1
Blood bilirubin increased ^† 1	1/73 (1.37%)	1	3/53 (5.66%)	3	0/45 (0.00%)	0	6/178 (3.37%)	11	2/179 (1.12%)	5	0/53 (0.00%)	0	0/45 (0.00%)	0
Blood cholesterol increased ^† 1	0/73 (0.00%)	0	2/53 (3.77%)	2	3/45 (6.67%)	3	5/178 (2.81%)	9	7/179 (3.91%)	14	0/53 (0.00%)	0	0/45 (0.00%)	0
Lymphocyte count decreased ^† 1	4/73 (5.48%)	4	3/53 (5.66%)	4	2/45 (4.44%)	2	6/178 (3.37%)	17	7/179 (3.91%)	8	0/53 (0.00%)	0	0/45 (0.00%)	0
Neutrophil count decreased ^† 1	3/73 (4.11%)	3	3/53 (5.66%)	4	4/45 (8.89%)	5	2/178 (1.12%)	10	1/179 (0.56%)	5	0/53 (0.00%)	0	0/45 (0.00%)	0
Platelet count decreased ^† 1	5/73 (6.85%)	7	4/53 (7.55%)	9	5/45 (11.11%)	8	2/178 (1.12%)	9	5/179 (2.79%)	9	0/53 (0.00%)	0	0/45 (0.00%)	0
White blood cell count decreased ^† 1	5/73 (6.85%)	6	3/53 (5.66%)	3	3/45 (6.67%)	3	4/178 (2.25%)	12	3/179 (1.68%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Blood creatinine increased ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	7	2/45 (4.44%)	2
Lipase increased ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	3	1/45 (2.22%)	1
Metabolism and nutrition disorders
Decreased appetite ^† 1	20/73 (27.40%)	21	8/53 (15.09%)	10	11/45 (24.44%)	12	36/178 (20.22%)	43	51/179 (28.49%)	55	9/53 (16.98%)	9	8/45 (17.78%)	8
Hyperglycaemia ^† 1	2/73 (2.74%)	2	5/53 (9.43%)	9	3/45 (6.67%)	3	12/178 (6.74%)	21	11/179 (6.15%)	21	3/53 (5.66%)	7	1/45 (2.22%)	3
Hypokalaemia ^† 1	3/73 (4.11%)	3	4/53 (7.55%)	5	3/45 (6.67%)	3	9/178 (5.06%)	9	8/179 (4.47%)	10	4/53 (7.55%)	7	3/45 (6.67%)	3
Hyponatraemia ^† 1	4/73 (5.48%)	6	3/53 (5.66%)	3	2/45 (4.44%)	3	19/178 (10.67%)	28	10/179 (5.59%)	11	6/53 (11.32%)	11	3/45 (6.67%)	4
Dehydration ^† 1	2/73 (2.74%)	3	3/53 (5.66%)	7	3/45 (6.67%)	4	7/178 (3.93%)	15	6/179 (3.35%)	7	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypertriglyceridaemia ^† 1	0/73 (0.00%)	0	4/53 (7.55%)	5	5/45 (11.11%)	7	7/178 (3.93%)	18	10/179 (5.59%)	25	0/53 (0.00%)	0	0/45 (0.00%)	0
Hypoalbuminaemia ^† 1	5/73 (6.85%)	5	3/53 (5.66%)	4	2/45 (4.44%)	2	5/178 (2.81%)	6	12/179 (6.70%)	13	0/53 (0.00%)	0	0/45 (0.00%)	0
Hyperkalaemia ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	4/53 (7.55%)	4	0/45 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	5/73 (6.85%)	6	6/53 (11.32%)	7	7/45 (15.56%)	9	36/178 (20.22%)	52	24/179 (13.41%)	37	9/53 (16.98%)	13	8/45 (17.78%)	9
Back pain ^† 1	8/73 (10.96%)	10	5/53 (9.43%)	5	6/45 (13.33%)	6	24/178 (13.48%)	31	21/179 (11.73%)	27	3/53 (5.66%)	3	2/45 (4.44%)	2
Musculoskeletal pain ^† 1	3/73 (4.11%)	3	4/53 (7.55%)	4	1/45 (2.22%)	1	18/178 (10.11%)	20	15/179 (8.38%)	15	4/53 (7.55%)	5	2/45 (4.44%)	2
Myalgia ^† 1	3/73 (4.11%)	3	4/53 (7.55%)	4	4/45 (8.89%)	7	19/178 (10.67%)	23	14/179 (7.82%)	15	3/53 (5.66%)	3	3/45 (6.67%)	3
Pain in extremity ^† 1	2/73 (2.74%)	2	6/53 (11.32%)	6	5/45 (11.11%)	5	18/178 (10.11%)	25	19/179 (10.61%)	25	4/53 (7.55%)	4	1/45 (2.22%)	4
Bone pain ^† 1	1/73 (1.37%)	1	2/53 (3.77%)	10	3/45 (6.67%)	3	2/178 (1.12%)	2	8/179 (4.47%)	8	0/53 (0.00%)	0	0/45 (0.00%)	0
Muscular weakness ^† 1	3/73 (4.11%)	3	5/53 (9.43%)	6	2/45 (4.44%)	3	5/178 (2.81%)	5	9/179 (5.03%)	11	0/53 (0.00%)	0	0/45 (0.00%)	0
Muscle spasms ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	1/53 (1.89%)	1	3/45 (6.67%)	6
Neck pain ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	5/53 (9.43%)	5	1/45 (2.22%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain ^† 1	4/73 (5.48%)	4	4/53 (7.55%)	4	3/45 (6.67%)	3	2/178 (1.12%)	2	8/179 (4.47%)	8	0/53 (0.00%)	0	0/45 (0.00%)	0
Melanocytic naevus ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	5	0/45 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	9/73 (12.33%)	9	4/53 (7.55%)	4	3/45 (6.67%)	3	19/178 (10.67%)	25	18/179 (10.06%)	27	3/53 (5.66%)	4	7/45 (15.56%)	7
Headache ^† 1	8/73 (10.96%)	8	9/53 (16.98%)	11	7/45 (15.56%)	10	21/178 (11.80%)	33	30/179 (16.76%)	45	8/53 (15.09%)	11	6/45 (13.33%)	10
Dysgeusia ^† 1	2/73 (2.74%)	2	5/53 (9.43%)	5	4/45 (8.89%)	4	3/178 (1.69%)	3	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Neuropathy peripheral ^† 1	6/73 (8.22%)	6	7/53 (13.21%)	7	5/45 (11.11%)	7	4/178 (2.25%)	4	3/179 (1.68%)	3	0/53 (0.00%)	0	0/45 (0.00%)	0
Paraesthesia ^† 1	3/73 (4.11%)	3	5/53 (9.43%)	6	3/45 (6.67%)	3	4/178 (2.25%)	4	4/179 (2.23%)	4	0/53 (0.00%)	0	0/45 (0.00%)	0
Peripheral sensory neuropathy ^† 1	1/73 (1.37%)	1	2/53 (3.77%)	2	3/45 (6.67%)	3	1/178 (0.56%)	1	2/179 (1.12%)	2	0/53 (0.00%)	0	0/45 (0.00%)	0
Tremor ^† 1	0/73 (0.00%)	0	1/53 (1.89%)	1	3/45 (6.67%)	3	3/178 (1.69%)	3	5/179 (2.79%)	5	0/53 (0.00%)	0	0/45 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	4/73 (5.48%)	6	4/53 (7.55%)	4	1/45 (2.22%)	1	10/178 (5.62%)	10	8/179 (4.47%)	8	3/53 (5.66%)	3	1/45 (2.22%)	1
Insomnia ^† 1	8/73 (10.96%)	8	2/53 (3.77%)	2	3/45 (6.67%)	3	9/178 (5.06%)	10	11/179 (6.15%)	12	3/53 (5.66%)	3	1/45 (2.22%)	1
Depression ^† 1	4/73 (5.48%)	4	4/53 (7.55%)	4	1/45 (2.22%)	1	7/178 (3.93%)	7	12/179 (6.70%)	13	0/53 (0.00%)	0	0/45 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	9/73 (12.33%)	9	13/53 (24.53%)	13	6/45 (13.33%)	8	37/178 (20.79%)	50	42/179 (23.46%)	50	7/53 (13.21%)	7	5/45 (11.11%)	6
Dyspnoea ^† 1	9/73 (12.33%)	10	10/53 (18.87%)	10	1/45 (2.22%)	1	18/178 (10.11%)	20	29/179 (16.20%)	33	7/53 (13.21%)	7	4/45 (8.89%)	4
Pleural effusion ^† 1	4/73 (5.48%)	4	1/53 (1.89%)	1	0/45 (0.00%)	0	3/178 (1.69%)	3	3/179 (1.68%)	3	4/53 (7.55%)	4	1/45 (2.22%)	1
Skin and subcutaneous tissue disorders
Night sweats ^† 1	2/73 (2.74%)	2	4/53 (7.55%)	5	3/45 (6.67%)	4	4/178 (2.25%)	4	10/179 (5.59%)	11	1/53 (1.89%)	1	4/45 (8.89%)	4
Pruritus ^† 1	5/73 (6.85%)	6	4/53 (7.55%)	4	6/45 (13.33%)	6	49/178 (27.53%)	77	57/179 (31.84%)	74	6/53 (11.32%)	7	5/45 (11.11%)	5
Rash ^† 1	6/73 (8.22%)	7	4/53 (7.55%)	5	3/45 (6.67%)	3	29/178 (16.29%)	38	33/179 (18.44%)	49	11/53 (20.75%)	15	7/45 (15.56%)	9
Rash maculo-papular ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	10/178 (5.62%)	11	18/179 (10.06%)	23	3/53 (5.66%)	4	1/45 (2.22%)	1
Alopecia ^† 1	10/73 (13.70%)	10	15/53 (28.30%)	18	11/45 (24.44%)	11	7/178 (3.93%)	8	2/179 (1.12%)	4	0/53 (0.00%)	0	0/45 (0.00%)	0
Dry skin ^† 1	4/73 (5.48%)	4	1/53 (1.89%)	1	0/45 (0.00%)	0	18/178 (10.11%)	24	18/179 (10.06%)	18	0/53 (0.00%)	0	0/45 (0.00%)	0
Erythema ^† 1	2/73 (2.74%)	2	2/53 (3.77%)	2	1/45 (2.22%)	2	10/178 (5.62%)	12	7/179 (3.91%)	8	0/53 (0.00%)	0	0/45 (0.00%)	0
Vitiligo ^† 1	0/73 (0.00%)	0	2/53 (3.77%)	2	1/45 (2.22%)	1	14/178 (7.87%)	19	16/179 (8.94%)	19	0/53 (0.00%)	0	0/45 (0.00%)	0
Vascular disorders
Hypotension ^† 1	1/73 (1.37%)	1	0/53 (0.00%)	0	0/45 (0.00%)	0	5/178 (2.81%)	7	11/179 (6.15%)	11	2/53 (3.77%)	2	3/45 (6.67%)	5
Hypertension ^† 1	1/73 (1.37%)	1	2/53 (3.77%)	2	1/45 (2.22%)	1	2/178 (1.12%)	2	9/179 (5.03%)	9	0/53 (0.00%)	0	0/45 (0.00%)	0
Deep vein thrombosis ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	3	0/45 (0.00%)	0
Lymphoedema ^† 1	0/73 (0.00%)	0	0/53 (0.00%)	0	0/45 (0.00%)	0	0/178 (0.00%)	0	0/179 (0.00%)	0	3/53 (5.66%)	3	1/45 (2.22%)	1
1 Term from vocabulary, MedDRA 21.1 † 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 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication timelines.

Results Point of Contact

Layout table for Results Point of Contact information

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

Publications of Results:

Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. doi: 10.1016/j.ejca.2017.07.022.

Other Publications:

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.

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.

Robert C, Hwu WJ, Hamid O, Ribas A, Weber JS, Daud AI, Hodi FS, Wolchok JD, Mitchell TC, Hersey P, Dronca R, Joseph RW, Boutros C, Min L, Long GV, Schachter J, Puzanov I, Dummer R, Lin J, Ibrahim N, Diede SJ, Carlino MS, Joshua AM. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Eur J Cancer. 2021 Feb;144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.

Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15. Erratum In: Eur J Cancer. 2021 Feb;144:400.

van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, Kang SP, Ibrahim N, Ebbinghaus S. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma? J Immunother Cancer. 2019 Feb 8;7(1):39. doi: 10.1186/s40425-019-0513-4.

Hamid O, Robert C, Ribas A, Hodi FS, Walpole E, Daud A, Arance AS, Brown E, Hoeller C, Mortier L, Schachter J, Long J, Ebbinghaus S, Ibrahim N, Butler M. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer. 2018 Sep;119(6):670-674. doi: 10.1038/s41416-018-0207-6. Epub 2018 Sep 11.

Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. doi: 10.1016/j.ejca.2016.07.018. Epub 2016 Sep 2.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT01704287
Other Study ID Numbers:	P08719 MK-3475-002 ( Other Identifier: Merck ) 2012-003030-17 ( EudraCT Number ) KEYNOTE-002 ( Other Identifier: Merck ) P08719 ( Other Identifier: Schering Plough )
First Submitted:	October 8, 2012
First Posted:	October 11, 2012
Results First Submitted:	October 17, 2016
Results First Posted:	March 28, 2017
Last Update Posted:	May 18, 2020

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