Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)

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ClinicalTrials.gov Identifier: NCT01866319

Recruitment Status : Completed

First Posted : May 31, 2013

Results First Posted : January 14, 2016

Last Update Posted : June 2, 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: None (Open Label); Primary Purpose: Treatment
Condition	Melanoma
Interventions	Biological: Pembrolizumab Biological: Ipilimumab
Enrollment	834

Participant Flow

Recruitment Details	Participants with advanced melanoma were recruited to receive ipilimumab once every 3 weeks (Q3W), or a primary course of pembrolizumab administered every 2 weeks (Q2W) or every 3 weeks (Q3W).
Pre-assignment Details	834 participants were randomized 1:1:1 to receive ipilimumab Q3W, pembrolizumab Q2W, or pembrolizumab Q3W. For participants receiving pembrolizumab, all safety and efficacy results data reported are for the primary pembrolizumab course received.


Arm/Group Title	Ipilimumab	Pembrolizumab Q2W	Pembrolizumab Q3W
Arm/Group Description	Participants received ipilimumab, 3...	Participants received pembrolizumab...	Participants received pembrolizumab...
Arm/Group Description	Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).	Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.	Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
Period Title: Overall Study
Started	278	279	277
Treated	256	278	277
Completed	71	101	97
Not Completed	207	178	180
Reason Not Completed
Adverse Event	12	5	9
Clinical progression	3	2	2
Death	153	154	147
Lost to Follow-up	6	3	8
Physician Decision	1	0	1
Protocol Violation	0	0	1
Withdrawal by Subject	32	14	12

Baseline Characteristics

Arm/Group Title		Ipilimumab	Pembrolizumab Q2W	Pembrolizumab Q3W	Total
Arm/Group Description		Participants received ipilimumab, 3...	Participants received pembrolizumab...	Participants received pembrolizumab...	Total of all reporting groups
Arm/Group Description		Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).	Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.	Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.	Total of all reporting groups
Overall Number of Baseline Participants		278	279	277	834
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The Intent-to-Treat (ITT) population consisted of all randomized participants. Participants were included in the group to which they were randomized for Baseline Characteristics.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	278 participants	279 participants	277 participants	834 participants
		59.9 (14.2)	59.9 (14.6)	61.2 (13.6)	60.3 (14.1)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	278 participants	279 participants	277 participants	834 participants
	Female	116 41.7%	118 42.3%	103 37.2%	337 40.4%
	Male	162 58.3%	161 57.7%	174 62.8%	497 59.6%

Outcome Measures

1.Primary Outcome


Title	Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO)
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 disease progression, based on blinded Independent Radiology plus Oncology review (IRO) using RECIST 1.1, or death due to any cause, whichever occurred first. Disease progression was defined as a 20% or greater increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of new lesions. The primary analysis of PFS was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.
Time Frame	Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)

Outcome Measure Data

Analysis Population Description

The ITT population, comprising all participants as randomized to a study arm.


Arm/Group Title	Ipilimumab	Pembrolizumab Q2W	Pembrolizumab Q3W
Arm/Group Description:	Participants received ipilimumab, 3...	Participants received pembrolizumab...	Participants received pembrolizumab...
Arm/Group Description:	Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).	Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.	Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
Overall Number of Participants Analyzed	278	279	277
Median (95% Confidence Interval) Unit of Measure: Months
	2.8 (2.8 to 2.9)	5.5 (3.4 to 6.9)	4.1 (2.9 to 6.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q2W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.00001
	Comments	[Not Specified]
	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 0.72
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.00001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95% 0.47 to 0.72
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Q2W, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.75869
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.77 to 1.21
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Percentage of Participants With Overall Survival (OS) at 12 Months
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. The percentage of participants with OS (OS rate) at 12 months was reported for each arm. The reported percentage was estimated using a product-limit (Kaplan-Meier) method for censored data; data were censored at the date of cut-off. The primary analysis of OS was performed at the time of the second protocol pre-specified statistical analysis, with data cut-off of 03-Mar-2015.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The ITT population, comprising all participants as randomized to a study arm.


Arm/Group Title	Ipilimumab	Pembrolizumab Q2W	Pembrolizumab Q3W
Arm/Group Description:	Participants received ipilimumab, 3...	Participants received pembrolizumab...	Participants received pembrolizumab...
Arm/Group Description:	Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).	Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.	Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
Overall Number of Participants Analyzed	278	279	277
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	58.2 (51.8 to 64.0)	74.1 (68.5 to 78.9)	68.4 (62.5 to 73.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q2W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00052
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95% 0.47 to 0.83
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00358
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95% 0.52 to 0.90
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Q2W, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.51319
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	95% 0.67 to 1.22
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO
Description	ORR was defined as the percentage of the participants with a best tumo...
Description	ORR was defined as the percentage of the participants with a best tumor response of complete response (CR: disappearance of all target lesions with any pathological lymph nodes having a reduction in short axis to <10 mm) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions), based on IRO using RECIST 1.1. The primary analysis of ORR was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.
Time Frame	Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)

Outcome Measure Data

Analysis Population Description

The ITT population, comprising all participants as randomized to a study arm.


Arm/Group Title	Ipilimumab	Pembrolizumab Q2W	Pembrolizumab Q3W
Arm/Group Description:	Participants received ipilimumab, 3...	Participants received pembrolizumab...	Participants received pembrolizumab...
Arm/Group Description:	Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).	Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.	Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
Overall Number of Participants Analyzed	278	279	277
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	11.9 (8.3 to 16.3)	33.7 (28.2 to 39.6)	32.9 (27.4 to 38.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q2W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00013
	Comments	[Not Specified]
	Method	Miettinen & Nurmimen
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Percent difference
	Estimated Value	16.1
	Confidence Interval	(2-Sided) 95% 7.8 to 24.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.00002
	Comments	[Not Specified]
	Method	Miettinen & Nurmimen
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Percent difference
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95% 9.5 to 25.6
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab Q2W, Pembrolizumab Q3W
	Comments	Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.82636
	Comments	[Not Specified]
	Method	Miettinen & Nurmimen
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Percent difference
	Estimated Value	-1.1
	Confidence Interval	95% -10.6 to 8.6
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Up to approximately 69 months (through End of Trial Analysis data cut-off date of 03-Jun-2019)
Adverse Event Reporting Description	All-Cause Mortality table includes all randomized participants. Serious and Other adverse events (AEs) tables include all randomized participants who received at least 1 dose of study drug. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Arm/Group Title	Ipilimumab		Pembrolizumab Q2W		Pembrolizumab Q3W
Arm/Group Description	Participants received ipilimumab, 3...		Participants received pembrolizumab...		Participants received pembrolizumab...
Arm/Group Description	Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).		Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.		Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
All-Cause Mortality
	Ipilimumab		Pembrolizumab Q2W		Pembrolizumab Q3W
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	173/278 (62.23%)		166/279 (59.50%)		162/277 (58.48%)
Serious Adverse Events Serious Adverse Events
	Ipilimumab		Pembrolizumab Q2W		Pembrolizumab Q3W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/256 (30.08%)		89/278 (32.01%)		90/277 (32.49%)
Blood and lymphatic system disorders
Anaemia ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	2/277 (0.72%)	2
Anaemia aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	3/277 (1.08%)	3
Lymph nodes enlarged ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Thrombocytopenia ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	2/277 (0.72%)	2
Cardiac disorders
Acute coronary syndrome ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Angina unstable ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Atrial fibrillation ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Atrial flutter ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Cardiac failure congestive ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Congestive cardiac failure aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	2
Decompensation cardiac ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	2/277 (0.72%)	2
Heart attack ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Paroxysmal atrial fibrillation ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Pericardial effusion ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Congenital, familial and genetic disorders
Pyloric stenosis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Ear and labyrinth disorders
Hearing impaired ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Endocrine disorders
Adrenal insufficiency ^† 1	1/256 (0.39%)	1	2/278 (0.72%)	2	0/277 (0.00%)	0
Adrenomegaly ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypophysitis ^† 1	2/256 (0.78%)	2	1/278 (0.36%)	1	1/277 (0.36%)	1
Hypopituitarism ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypothyroidism ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Panhypopituitarism ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Eye disorders
Diplopia ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Neovascular glaucoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Papilloedema ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Gastrointestinal disorders
Abdominal distension ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Abdominal pain ^† 1	2/256 (0.78%)	2	1/278 (0.36%)	1	2/277 (0.72%)	2
Abdominal pain lower ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Anal fistula ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Autoimmune colitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Autoimmune pancreatitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Blood in stool ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Colitis ^† 1	16/256 (6.25%)	18	6/278 (2.16%)	6	6/277 (2.17%)	6
Constipation ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	1/277 (0.36%)	1
Diarrhoea ^† 1	9/256 (3.52%)	9	7/278 (2.52%)	7	3/277 (1.08%)	3
Enteritis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Enterocolitis ^† 1	2/256 (0.78%)	2	0/278 (0.00%)	0	0/277 (0.00%)	0
Gastritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	2/277 (0.72%)	2
Gastrooesophagitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Haemorrhage of digestive tract ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Ileus ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Intestinal obstruction ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	3	0/277 (0.00%)	0
Intestinal stenosis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Intussusception ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Lower gastrointestinal bleeding ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Lower gastrointestinal haemorrhage ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Mouth necrosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Nausea ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Pancreatitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Pancreatitis acute ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Pancreatitis aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Partial small intestinal obstruction ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Reflux oesophagitis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Sigmoiditis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Small intestinal obstruction ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Vomiting ^† 1	2/256 (0.78%)	2	0/278 (0.00%)	0	0/277 (0.00%)	0
General disorders
Anasarca ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Asthenia ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Cardiac death ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Face oedema ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Fatigue aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Fever ^† 1	4/256 (1.56%)	4	1/278 (0.36%)	1	0/277 (0.00%)	0
General body pain ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
General physical health deterioration ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Malaise ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	1/277 (0.36%)	1
Reduced general condition ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Unknown cause of death ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	2/256 (0.78%)	2	4/278 (1.44%)	4	1/277 (0.36%)	1
Bile duct obstruction ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Biliary colic ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Biliary dilatation ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Cholangitis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Cholecystitis ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	0/277 (0.00%)	0
Cytolytic hepatitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Drug-induced hepatitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	2
Hepatic cytolysis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Hepatitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Hepatitis toxic ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Obstructive jaundice ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Immune system disorders
Anaphylactoid reaction ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Drug hypersensitivity ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypersensitivity reaction ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Infections and infestations
Bladder infection ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Bronchial infection ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Cellulitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	2/277 (0.72%)	2
Cellulitis aggravated ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Cellulitis of oral soft tissues ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Cellulitis of upper arm ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Central line infection ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Clostridium difficile colitis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Colonic abscess ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Cytomegalovirus infection ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Encephalitis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Erysipelas ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	1/277 (0.36%)	1
Escherichia bacteraemia ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Gastroenteritis ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	0/277 (0.00%)	0
Infection ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Klebsiella sepsis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Lung infection ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	2/277 (0.72%)	2
Meningoencephalitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Myelitis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Pneumonia ^† 1	1/256 (0.39%)	1	2/278 (0.72%)	2	1/277 (0.36%)	1
Pneumonia viral ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Pseudomembranous colitis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Pyelonephritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Respiratory tract infection ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Sepsis ^† 1	2/256 (0.78%)	2	2/278 (0.72%)	2	2/277 (0.72%)	2
Septic shock ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Septicaemia gram-negative NOS ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Sinusitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Soft tissue infection ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Urinary tract infection ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	1/277 (0.36%)	1
Injury, poisoning and procedural complications
Facial bones fracture ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Radiation necrosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Rib fracture ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Shoulder injury ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Wound breakdown ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	2/256 (0.78%)	2	1/278 (0.36%)	1	1/277 (0.36%)	1
Aspartate aminotransferase increased ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	2/277 (0.72%)	2
Bilirubin total increased ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Intraocular pressure decreased ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Liver function test abnormal ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Metabolism and nutrition disorders
Dehydration ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Diabetic ketoacidosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Failure to thrive ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Gout ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypercalcaemia ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Hypoalbuminaemia ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypokalaemia ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	1/277 (0.36%)	1
Hyponatraemia ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	2/277 (0.72%)	2
Hyponatremia aggravated ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Metabolic disorder ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Type 1 diabetes mellitus ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Musculoskeletal and connective tissue disorders
Back pain aggravated ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Hips osteoarthritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Low back pain ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Myalgia ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Pain in heel ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Pain in leg ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	1/277 (0.36%)	1
Pathologic fracture of femur ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Pathologic fracture of humerus ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	0/277 (0.00%)	0
Pathological fracture ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Prolapsed lumbar disc ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Psoriatic arthritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Seronegative arthritis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Unilateral leg pain ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell chronic lymphocytic leukaemia ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Basal cell carcinoma ^† 1	0/256 (0.00%)	0	5/278 (1.80%)	7	2/277 (0.72%)	2
Basal squamous cell carcinoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Desmoplastic melanoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Epidermoid carcinoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Huerthle cell carcinoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Intra-epidermal carcinoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Intracranial tumour bleeding ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Intracranial tumour haemorrhage ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Lung neoplasm malignant ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Lymphangiosis carcinomatosa ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Melanoma ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Metastases to brain ^† 1	2/256 (0.78%)	2	1/278 (0.36%)	1	1/277 (0.36%)	1
Metastatic malignant melanoma ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	0/277 (0.00%)	0
Neoplasm malignant ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Papillary thyroid cancer ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Papilloma ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Prostate cancer ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Renal cell carcinoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Signet-ring cell adenocarcinoma gastric ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Squamous cell carcinoma ^† 1	1/256 (0.39%)	1	2/278 (0.72%)	2	1/277 (0.36%)	1
Squamous cell carcinoma of skin ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	1/277 (0.36%)	1
Superficial basal cell carcinoma ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Thyroid papillary carcinoma ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Tumour bleeding ^† 1	3/256 (1.17%)	3	0/278 (0.00%)	0	0/277 (0.00%)	0
Tumour pain ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Nervous system disorders
Bell's palsy ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Brain oedema ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Carotid artery stenosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Cerebral ischaemia ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Cerebral oedema ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Cerebrovascular accident ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Convulsions aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Dizziness ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Encephalopathy ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Epilepsy ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Guillain-Barre syndrome ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Haemorrhage brain ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Haemorrhage intracranial ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Haemorrhagic stroke ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Horner's syndrome ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Hydrocephalus ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Paraneoplastic limbic encephalitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Partial seizures ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Sciatica ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Seizure ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Spinal cord compression ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Syncope ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Transient ischaemic attack ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Vasogenic cerebral oedema ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Psychiatric disorders
Acute delirium ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Completed suicide ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Confusion ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Depression aggravated ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Dysphoria ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Mental status changes ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Acute renal insufficiency ^† 1	0/256 (0.00%)	0	2/278 (0.72%)	2	1/277 (0.36%)	2
Autoimmune nephritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Hydronephrosis ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Nephritis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Nephritis interstitial ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	2/277 (0.72%)	2
Renal disorder ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Renal failure ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	1/277 (0.36%)	1
Renal insufficiency ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	1/277 (0.36%)	1
Tubulointerstitial nephritis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Urinary retention ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Reproductive system and breast disorders
Prostatitis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	2	0/277 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Chronic obstructive pulmonary disease exacerbation ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	2
Cough ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	1/277 (0.36%)	1
Dyspnoea ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Dyspnoea exacerbated ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Haemoptysis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	2/277 (0.72%)	2
Hypoxia ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Pleural effusion ^† 1	1/256 (0.39%)	2	1/278 (0.36%)	1	1/277 (0.36%)	1
Pneumonitis ^† 1	1/256 (0.39%)	1	1/278 (0.36%)	1	4/277 (1.44%)	4
Pneumothorax ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Pulmonary embolism ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	4/277 (1.44%)	4
Pulmonary thrombosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Skin and subcutaneous tissue disorders
Bullous lichen planus ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Bullous pemphigoid ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Drug rash ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Rash ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	2/277 (0.72%)	2
Vascular disorders
Aortic stenosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Arterial stenosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Arterial thrombosis ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Deep vein thrombosis ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Haematoma ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Hypotension ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Lymphoedema ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Orthostatic hypotension ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Peripheral vascular disorder ^† 1	0/256 (0.00%)	0	0/278 (0.00%)	0	1/277 (0.36%)	1
Poor venous access ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Superior vena cava occlusion ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
Thrombosis leg ^† 1	1/256 (0.39%)	1	0/278 (0.00%)	0	0/277 (0.00%)	0
Vein disorder ^† 1	0/256 (0.00%)	0	1/278 (0.36%)	1	0/277 (0.00%)	0
1 Term from vocabulary, MedDRA 22.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ipilimumab		Pembrolizumab Q2W		Pembrolizumab Q3W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	220/256 (85.94%)		257/278 (92.45%)		247/277 (89.17%)
Blood and lymphatic system disorders
Anaemia ^† 1	12/256 (4.69%)	14	34/278 (12.23%)	44	23/277 (8.30%)	28
Endocrine disorders
Hyperthyroidism ^† 1	6/256 (2.34%)	6	17/278 (6.12%)	19	12/277 (4.33%)	12
Hypothyroidism ^† 1	5/256 (1.95%)	5	29/278 (10.43%)	31	25/277 (9.03%)	26
Gastrointestinal disorders
Abdominal pain ^† 1	16/256 (6.25%)	19	29/278 (10.43%)	37	18/277 (6.50%)	19
Constipation ^† 1	29/256 (11.33%)	32	53/278 (19.06%)	78	39/277 (14.08%)	47
Diarrhoea ^† 1	69/256 (26.95%)	91	82/278 (29.50%)	162	76/277 (27.44%)	116
Dry mouth ^† 1	1/256 (0.39%)	1	26/278 (9.35%)	27	20/277 (7.22%)	21
Nausea ^† 1	55/256 (21.48%)	66	73/278 (26.26%)	90	70/277 (25.27%)	88
Vomiting ^† 1	31/256 (12.11%)	35	45/278 (16.19%)	66	27/277 (9.75%)	32
General disorders
Asthenia ^† 1	26/256 (10.16%)	29	45/278 (16.19%)	92	41/277 (14.80%)	56
Fatigue ^† 1	73/256 (28.52%)	78	90/278 (32.37%)	125	85/277 (30.69%)	116
Fever ^† 1	20/256 (7.81%)	22	29/278 (10.43%)	40	21/277 (7.58%)	35
Flu-like symptoms ^† 1	8/256 (3.13%)	9	21/278 (7.55%)	23	14/277 (5.05%)	27
Infections and infestations
Common cold syndrome ^† 1	9/256 (3.52%)	9	21/278 (7.55%)	32	15/277 (5.42%)	18
Upper respiratory tract infection ^† 1	11/256 (4.30%)	11	31/278 (11.15%)	43	21/277 (7.58%)	25
Urinary tract infection ^† 1	10/256 (3.91%)	11	22/278 (7.91%)	33	14/277 (5.05%)	19
Investigations
Alanine aminotransferase increased ^† 1	12/256 (4.69%)	13	21/278 (7.55%)	32	16/277 (5.78%)	19
Aspartate aminotransferase increased ^† 1	12/256 (4.69%)	13	22/278 (7.91%)	35	12/277 (4.33%)	17
Lactate dehydrogenase increased ^† 1	6/256 (2.34%)	6	14/278 (5.04%)	25	6/277 (2.17%)	11
Weight decreased ^† 1	13/256 (5.08%)	13	20/278 (7.19%)	21	26/277 (9.39%)	28
Metabolism and nutrition disorders
Anorexia ^† 1	24/256 (9.38%)	27	31/278 (11.15%)	39	35/277 (12.64%)	36
Hypokalaemia ^† 1	5/256 (1.95%)	7	16/278 (5.76%)	34	13/277 (4.69%)	14
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	18/256 (7.03%)	18	41/278 (14.75%)	63	39/277 (14.08%)	42
Back pain ^† 1	8/256 (3.13%)	8	29/278 (10.43%)	32	11/277 (3.97%)	12
Knee pain ^† 1	6/256 (2.34%)	6	15/278 (5.40%)	21	8/277 (2.89%)	8
Low back pain ^† 1	5/256 (1.95%)	5	17/278 (6.12%)	19	12/277 (4.33%)	14
Myalgia ^† 1	8/256 (3.13%)	8	32/278 (11.51%)	38	15/277 (5.42%)	18
Shoulder pain ^† 1	8/256 (3.13%)	9	21/278 (7.55%)	26	12/277 (4.33%)	12
Nervous system disorders
Dizziness ^† 1	9/256 (3.52%)	9	27/278 (9.71%)	34	22/277 (7.94%)	26
Headache ^† 1	27/256 (10.55%)	29	45/278 (16.19%)	72	33/277 (11.91%)	58
Psychiatric disorders
Anxiety ^† 1	4/256 (1.56%)	4	14/278 (5.04%)	14	10/277 (3.61%)	10
Insomnia ^† 1	14/256 (5.47%)	14	28/278 (10.07%)	33	20/277 (7.22%)	20
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	16/256 (6.25%)	17	58/278 (20.86%)	75	43/277 (15.52%)	48
Dry cough ^† 1	2/256 (0.78%)	2	9/278 (3.24%)	10	15/277 (5.42%)	16
Dyspnoea ^† 1	15/256 (5.86%)	16	30/278 (10.79%)	32	27/277 (9.75%)	27
Sore throat ^† 1	4/256 (1.56%)	5	16/278 (5.76%)	16	5/277 (1.81%)	5
Skin and subcutaneous tissue disorders
Dry skin ^† 1	6/256 (2.34%)	6	19/278 (6.83%)	20	17/277 (6.14%)	17
Pruritus ^† 1	65/256 (25.39%)	76	68/278 (24.46%)	99	59/277 (21.30%)	83
Rash ^† 1	28/256 (10.94%)	29	37/278 (13.31%)	55	36/277 (13.00%)	51
Rash maculo-papular ^† 1	8/256 (3.13%)	8	17/278 (6.12%)	23	10/277 (3.61%)	15
Vitiligo ^† 1	4/256 (1.56%)	4	34/278 (12.23%)	36	42/277 (15.16%)	45
1 Term from vocabulary, MedDRA 22.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation.

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:

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X. Epub 2017 Aug 16.

Other Publications:

Robert C,Schachter J,Long GV,Arance A,Grob JJ,Mortier L,Daud A,Carlino MS,McNeil C,Lotem M,Larkin J,Lorigan P,Neyns B,Blank CU,Hamid O,Mateus C,Shapira-Frommer R,Kosh M,Zhou H,Ibrahim N,Ebbinghaus S,Ribas A,KEYNOTE-006 investigators . Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Apr 19; PMID: 25891173

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

Hamid O, Robert C, Daud A, Carlino MS, Mitchell TC, Hersey P, Schachter J, Long GV, Hodi FS, Wolchok JD, Arance A, Grob JJ, Joshua AM, Weber JS, Mortier L, Jensen E, Diede SJ, Moreno BH, Ribas A. Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006. Eur J Cancer. 2021 Nov;157:391-402. doi: 10.1016/j.ejca.2021.08.013. Epub 2021 Sep 25.

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.

Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. doi: 10.1016/S1470-2045(19)30388-2. Epub 2019 Jul 22.

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.

Carlino MS, Long GV, Schadendorf D, Robert C, Ribas A, Richtig E, Nyakas M, Caglevic C, Tarhini A, Blank C, Hoeller C, Bar-Sela G, Barrow C, Wolter P, Zhou H, Emancipator K, Jensen EH, Ebbinghaus S, Ibrahim N, Daud A. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. Eur J Cancer. 2018 Sep;101:236-243. doi: 10.1016/j.ejca.2018.06.034. Epub 2018 Aug 7.

Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. doi: 10.1016/j.ejca.2017.08.032. Epub 2017 Oct 4.

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT01866319
Other Study ID Numbers:	3475-006 2012-004907-10 ( EudraCT Number ) MK-3475-006 ( Other Identifier: Merck Protocol Number )
First Submitted:	May 28, 2013
First Posted:	May 31, 2013
Results First Submitted:	December 9, 2015
Results First Posted:	January 14, 2016
Last Update Posted:	June 2, 2020

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