Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)

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ClinicalTrials.gov Identifier: NCT02578680

Recruitment Status : Completed

First Posted : October 19, 2015

Results First Posted : November 28, 2018

Last Update Posted : July 20, 2023

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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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Non-Small-Cell Lung Carcinoma
Interventions	Biological: Pembrolizumab 200 mg Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed Dietary Supplement: Folic acid 350-1000 μg Dietary Supplement: Vitamin B12 1000 μg Drug: Dexamethasone 4 mg Drug: Saline solution
Enrollment	616

Participant Flow

Recruitment Details
Pre-assignment Details	These interim results are based on a database cutoff date of 08-Nov-2017, at which time 372 participants were ongoing in the study. 67 participants randomized to receiving Control treatment had switched to receiving pembrolizumab monotherapy treatment. These interim results are for randomized treatment only.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab...	Participants received saline placeb...
Arm/Group Description	Participants received pembrolizumab (pembro) 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Period Title: Overall Study
Started	410	206
Treated	405	202
Switched to Pembrolizumab	0	67
Completed	0	0
Not Completed	410	206
Reason Not Completed
Death	124	104
Protocol Violation	1	1
Withdrawal by Parent/Guardian	1	0
Withdrawal by Subject	8	5
Ongoing in Study	276	96

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Control	Total
Arm/Group Description		Participants received pembro 200 mg...	Participants received saline placeb...	Total of all reporting groups
Arm/Group Description		Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.	Total of all reporting groups
Overall Number of Baseline Participants		410	206	616
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The Baseline Analysis Population consisted of all randomized participants.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	410 participants	206 participants	616 participants
		63.2 (9.4)	62.8 (9.1)	63.1 (9.3)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	410 participants	206 participants	616 participants
	Female	156 38.0%	97 47.1%	253 41.1%
	Male	254 62.0%	109 52.9%	363 58.9%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	410 participants	206 participants	616 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	10 2.4%	8 3.9%	18 2.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	11 2.7%	3 1.5%	14 2.3%
	White	387 94.4%	194 94.2%	581 94.3%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	2 0.5%	1 0.5%	3 0.5%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	410 participants	206 participants	616 participants
TPS <1%		127 31.0%	63 30.6%	190 30.8%
TPS ≥1%		260 63.4%	128 62.1%	388 63.0%
Not Evaluable		23 5.6%	15 7.3%	38 6.2%
		[1] Measure Description: Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from an archival or newly obtained biopsy. Participants with a TPS ≥1% were classified as PD-L1 positive and participants with a TPS <1% were classified as PD-L1 negative.
Platinum Chemotherapy ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	410 participants	206 participants	616 participants
Cisplatin		113 27.6%	58 28.2%	171 27.8%
Carboplatin		297 72.4%	148 71.8%	445 72.2%
		[1] Measure Description: Participants were classified according to the type of platinum chemotherapy the Investigator chose for them to receive: Cisplatin or Carboplatin.
Smoking Status ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	410 participants	206 participants	616 participants
Never Smoker		48 11.7%	25 12.1%	73 11.9%
Former/Current Smoker		362 88.3%	181 87.9%	543 88.1%
		[1] Measure Description: Participants were classified according to their smoking status: Never Smoker or Former/Current Smoker.

Outcome Measures

1.Primary Outcome


Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging
Description	PFS was defined as the time from randomization to the first documented...
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.
Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	410	206
Median (95% Confidence Interval) Unit of Measure: Months
	8.8 (7.6 to 9.2)	4.9 (4.7 to 5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Control
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	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	0.52
	Confidence Interval	(2-Sided) 95% 0.43 to 0.64
	Estimation Comments	Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.

2.Primary Outcome


Title	Overall Survival (OS)
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 without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS is presented.
Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	410	206
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (NA to NA)	11.3 (8.7 to 15.1)

[1]

NA=Median OS not reached NA=Lower Limit OS not reached NA=Upper Limit OS not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Control
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	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	0.49
	Confidence Interval	(2-Sided) 95% 0.38 to 0.64
	Estimation Comments	Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.

3.Secondary Outcome


Title	Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Description	ORR was defined as the percentage of participants in the analysis popu...
Description	ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.
Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	410	206
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	47.6 (42.6 to 52.5)	18.9 (13.8 to 25.0)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	H0:Difference in percentages=0 vs H1:Difference in percentages>0
	Method	Stratified Miettinen and Nurminen
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in Percentage vs. Control
	Estimated Value	28.5
	Confidence Interval	(2-Sided) 95% 21.1 to 35.4
	Estimation Comments	Miettinen and Nurminen method with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.

4.Secondary Outcome


Title	Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Description	For participants who demonstrated a confirmed CR (disappearance of all...
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until PD 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. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented.
Time Frame	From time of first documented evidence of CR or PR through database cutoff date of 08-Nov-2017 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who experienced a confirmed CR or confirmed PR.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	195	39
Median (Full Range) Unit of Measure: Months
	11.2 (1.1 to 18.0)	7.8 (2.1 to 16.4)

5.Secondary Outcome


Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a study partic...
Description	An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. For participants who switched from the Control group to receiving pembro, AEs that occurred after the first dose of pembro are excluded from this interim analysis, but will be included in the final analysis. The number of participants who experienced an AE is presented.
Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received ≥1 dose of study drug.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	405	202
Measure Type: Count of Participants Unit of Measure: Participants
	404 99.8%	200 99.0%

6.Secondary Outcome


Title	Number of Participants Who Discontinued Any Study Drug Due to an AE
Description	The number of participants who discontinued any randomized study drug ...
Description	The number of participants who discontinued any randomized study drug due to an AE is presented.
Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received ≥1 dose of study drug.


Arm/Group Title	Pembrolizumab	Control
Arm/Group Description:	Participants received pembro 200 mg...	Participants received saline placeb...
Arm/Group Description:	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed	405	202
Measure Type: Count of Participants Unit of Measure: Participants
	112 27.7%	30 14.9%

7.Other Pre-specified Outcome


Title	Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Up to 24 months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study drug, Other AEs: Up to 30 days after last dose of study drug
Adverse Event Reporting Description	Population: All participants receiving ≥1 dose of randomized study drug. Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study drug are excluded as AEs. For participants who switched from the Control group to receiving pembro, AEs occurring after 1st pembro dose are excluded from this interim analysis.

Arm/Group Title	Pembrolizumab		Control
Arm/Group Description	Participants received pembro 200 mg...		Participants received saline placeb...
Arm/Group Description	Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.		Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
All-Cause Mortality
	Pembrolizumab		Control
	Affected / at Risk (%)		Affected / at Risk (%)
Total	124/405 (30.62%)		105/202 (51.98%)
Serious Adverse Events Serious Adverse Events
	Pembrolizumab		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	202/405 (49.88%)		95/202 (47.03%)
Blood and lymphatic system disorders
Anaemia ^† 1	12/405 (2.96%)	13	10/202 (4.95%)	11
Disseminated intravascular coagulation ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Febrile neutropenia ^† 1	23/405 (5.68%)	25	4/202 (1.98%)	4
Leukopenia ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Neutropenia ^† 1	10/405 (2.47%)	10	1/202 (0.50%)	1
Pancytopenia ^† 1	4/405 (0.99%)	4	2/202 (0.99%)	3
Thrombocytopenia ^† 1	13/405 (3.21%)	14	5/202 (2.48%)	5
Cardiac disorders
Acute myocardial infarction ^† 1	1/405 (0.25%)	2	0/202 (0.00%)	0
Atrial fibrillation ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Atrial flutter ^† 1	0/405 (0.00%)	0	2/202 (0.99%)	2
Cardiac arrest ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Cardiac failure ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Cardiopulmonary failure ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Myocardial infarction ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Pericardial effusion ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pericarditis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Sinus tachycardia ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Stress cardiomyopathy ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Supraventricular tachycardia ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Tachyarrhythmia ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Ventricular arrhythmia ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Endocrine disorders
Adrenal insufficiency ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Hypothyroidism ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Abdominal pain upper ^† 1	1/405 (0.25%)	1	2/202 (0.99%)	2
Colitis ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Constipation ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Diarrhoea ^† 1	15/405 (3.70%)	17	6/202 (2.97%)	9
Duodenitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Gastroduodenitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Gastrointestinal perforation ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Impaired gastric emptying ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Intestinal ischaemia ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Intestinal pseudo-obstruction ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Intussusception ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Lip oedema ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Mesenteric artery embolism ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Nausea ^† 1	4/405 (0.99%)	4	6/202 (2.97%)	6
Neutropenic colitis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Oesophageal stenosis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Oesophagitis ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Pancreatitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pancreatitis acute ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pancreatitis chronic ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Small intestinal haemorrhage ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Stomatitis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Vomiting ^† 1	8/405 (1.98%)	9	5/202 (2.48%)	5
General disorders
Asthenia ^† 1	7/405 (1.73%)	7	0/202 (0.00%)	0
Chest pain ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Death ^† 1	3/405 (0.74%)	3	1/202 (0.50%)	1
Fatigue ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
General physical health deterioration ^† 1	4/405 (0.99%)	4	2/202 (0.99%)	3
Influenza like illness ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Localised oedema ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Malaise ^† 1	1/405 (0.25%)	1	2/202 (0.99%)	2
Mucosal inflammation ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Multiple organ dysfunction syndrome ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Oedema peripheral ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Pyrexia ^† 1	9/405 (2.22%)	10	3/202 (1.49%)	3
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Bile duct stone ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cholangitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cholangitis sclerosing ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cholecystitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Hepatitis ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Hepatotoxicity ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Immune system disorders
Cytokine release syndrome ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Infections and infestations
Abdominal sepsis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Bacteraemia ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Bacterial colitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Bronchitis ^† 1	4/405 (0.99%)	4	2/202 (0.99%)	2
CNS ventriculitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cellulitis ^† 1	5/405 (1.23%)	6	1/202 (0.50%)	2
Clostridium difficile colitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Diverticulitis ^† 1	1/405 (0.25%)	2	1/202 (0.50%)	1
Empyema ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Endocarditis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Erysipelas ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Folliculitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Gastroenteritis ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Herpes zoster ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Infected dermal cyst ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Infection ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Infectious pleural effusion ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Influenza ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Kidney infection ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Lower respiratory tract infection ^† 1	2/405 (0.49%)	2	3/202 (1.49%)	3
Lung abscess ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Lung infection ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Neutropenic sepsis ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Oral candidiasis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Otitis media ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Peritonitis ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Pneumocystis jirovecii pneumonia ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pneumonia ^† 1	23/405 (5.68%)	23	17/202 (8.42%)	19
Pneumonia bacterial ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pulmonary sepsis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Respiratory tract infection ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Salmonella bacteraemia ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Sepsis ^† 1	5/405 (1.23%)	5	2/202 (0.99%)	2
Septic shock ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Tuberculosis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Tuberculous pleurisy ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Upper respiratory tract infection ^† 1	6/405 (1.48%)	6	2/202 (0.99%)	5
Urinary tract infection ^† 1	4/405 (0.99%)	4	1/202 (0.50%)	1
Injury, poisoning and procedural complications
Accidental overdose ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Craniocerebral injury ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Fall ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Femoral neck fracture ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Femur fracture ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Limb traumatic amputation ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Lumbar vertebral fracture ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Spinal compression fracture ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Spinal fracture ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Toxicity to various agents ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Upper limb fracture ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Investigations
Alanine aminotransferase increased ^† 1	0/405 (0.00%)	0	2/202 (0.99%)	2
Blood calcium decreased ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Blood creatinine increased ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Blood magnesium decreased ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
C-reactive protein increased ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Hepatic enzyme increased ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Platelet count decreased ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Metabolism and nutrition disorders
Dehydration ^† 1	5/405 (1.23%)	6	2/202 (0.99%)	2
Hyperglycaemia ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Hypokalaemia ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Hypomagnesaemia ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Hyponatraemia ^† 1	1/405 (0.25%)	1	2/202 (0.99%)	2
Type 1 diabetes mellitus ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Type 2 diabetes mellitus ^† 1	2/405 (0.49%)	3	0/202 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	5/405 (1.23%)	5	0/202 (0.00%)	0
Back pain ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	2
Flank pain ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Groin pain ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Hypertrophic osteoarthropathy ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Muscle haemorrhage ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Muscular weakness ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Musculoskeletal chest pain ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Myalgia ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pain in extremity ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Pathological fracture ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain ^† 1	3/405 (0.74%)	3	2/202 (0.99%)	2
Malignant neoplasm progression ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Metastases to central nervous system ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Thyroid cancer ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Tracheal neoplasm ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Tumour pain ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Nervous system disorders
Balance disorder ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Brain stem infarction ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cerebral haemorrhage ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Cerebral infarction ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Cerebrovascular accident ^† 1	3/405 (0.74%)	3	0/202 (0.00%)	0
Dizziness ^† 1	4/405 (0.99%)	4	1/202 (0.50%)	1
Encephalopathy ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Haemorrhage intracranial ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Hydrocephalus ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Ischaemic stroke ^† 1	2/405 (0.49%)	3	1/202 (0.50%)	1
Lacunar stroke ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Lumbar radiculopathy ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Partial seizures ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	2
Seizure ^† 1	2/405 (0.49%)	2	1/202 (0.50%)	1
Syncope ^† 1	2/405 (0.49%)	2	2/202 (0.99%)	2
Transient ischaemic attack ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Vasculitis cerebral ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Product Issues
Device dislocation ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Confusional state ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Delirium ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Disorientation ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Major depression ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	8/405 (1.98%)	8	0/202 (0.00%)	0
Acute prerenal failure ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Autoimmune nephritis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Haematuria ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Nephritis ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Prerenal failure ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Renal failure ^† 1	1/405 (0.25%)	1	2/202 (0.99%)	2
Renal tubular necrosis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Tubulointerstitial nephritis ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Urinary tract obstruction ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Reproductive system and breast disorders
Balanoposthitis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Atelectasis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Chronic obstructive pulmonary disease ^† 1	4/405 (0.99%)	5	3/202 (1.49%)	3
Dyspnoea ^† 1	5/405 (1.23%)	5	5/202 (2.48%)	6
Epistaxis ^† 1	1/405 (0.25%)	1	1/202 (0.50%)	1
Haemoptysis ^† 1	3/405 (0.74%)	3	2/202 (0.99%)	2
Haemothorax ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Hiccups ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Obstructive airways disorder ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pleural effusion ^† 1	6/405 (1.48%)	7	4/202 (1.98%)	4
Pneumonia aspiration ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Pneumonitis ^† 1	12/405 (2.96%)	13	4/202 (1.98%)	4
Pneumothorax ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Pulmonary embolism ^† 1	5/405 (1.23%)	5	4/202 (1.98%)	4
Respiratory failure ^† 1	1/405 (0.25%)	1	3/202 (1.49%)	3
Skin and subcutaneous tissue disorders
Dermatitis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Diabetic foot ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Rash ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Rash papular ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Skin sensitisation ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Vascular disorders
Deep vein thrombosis ^† 1	2/405 (0.49%)	2	2/202 (0.99%)	2
Hypertension ^† 1	2/405 (0.49%)	2	0/202 (0.00%)	0
Jugular vein thrombosis ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
Peripheral artery occlusion ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Vena cava thrombosis ^† 1	1/405 (0.25%)	1	0/202 (0.00%)	0
Venous occlusion ^† 1	0/405 (0.00%)	0	1/202 (0.50%)	1
1 Term from vocabulary, MedDRA 20.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	393/405 (97.04%)		196/202 (97.03%)
Blood and lymphatic system disorders
Anaemia ^† 1	178/405 (43.95%)	227	88/202 (43.56%)	112
Leukopenia ^† 1	23/405 (5.68%)	26	13/202 (6.44%)	17
Neutropenia ^† 1	104/405 (25.68%)	192	48/202 (23.76%)	91
Thrombocytopenia ^† 1	64/405 (15.80%)	100	25/202 (12.38%)	36
Endocrine disorders
Hypothyroidism ^† 1	26/405 (6.42%)	34	5/202 (2.48%)	5
Eye disorders
Lacrimation increased ^† 1	69/405 (17.04%)	76	22/202 (10.89%)	23
Gastrointestinal disorders
Abdominal pain ^† 1	29/405 (7.16%)	37	11/202 (5.45%)	11
Abdominal pain upper ^† 1	24/405 (5.93%)	26	2/202 (0.99%)	2
Constipation ^† 1	139/405 (34.32%)	199	64/202 (31.68%)	83
Diarrhoea ^† 1	115/405 (28.40%)	156	40/202 (19.80%)	50
Dyspepsia ^† 1	24/405 (5.93%)	29	11/202 (5.45%)	11
Nausea ^† 1	223/405 (55.06%)	392	101/202 (50.00%)	180
Stomatitis ^† 1	35/405 (8.64%)	44	15/202 (7.43%)	20
Vomiting ^† 1	94/405 (23.21%)	160	43/202 (21.29%)	66
General disorders
Asthenia ^† 1	77/405 (19.01%)	121	49/202 (24.26%)	80
Chest pain ^† 1	34/405 (8.40%)	38	11/202 (5.45%)	13
Fatigue ^† 1	164/405 (40.49%)	258	77/202 (38.12%)	126
Mucosal inflammation ^† 1	35/405 (8.64%)	45	15/202 (7.43%)	22
Oedema peripheral ^† 1	78/405 (19.26%)	106	26/202 (12.87%)	35
Pyrexia ^† 1	74/405 (18.27%)	97	27/202 (13.37%)	40
Infections and infestations
Conjunctivitis ^† 1	31/405 (7.65%)	40	17/202 (8.42%)	31
Nasopharyngitis ^† 1	30/405 (7.41%)	40	10/202 (4.95%)	12
Upper respiratory tract infection ^† 1	35/405 (8.64%)	41	14/202 (6.93%)	15
Urinary tract infection ^† 1	28/405 (6.91%)	40	11/202 (5.45%)	16
Investigations
Alanine aminotransferase increased ^† 1	49/405 (12.10%)	62	17/202 (8.42%)	21
Aspartate aminotransferase increased ^† 1	38/405 (9.38%)	49	13/202 (6.44%)	14
Blood creatinine increased ^† 1	46/405 (11.36%)	69	16/202 (7.92%)	24
Weight decreased ^† 1	37/405 (9.14%)	40	15/202 (7.43%)	16
White blood cell count decreased ^† 1	26/405 (6.42%)	45	13/202 (6.44%)	20
Metabolism and nutrition disorders
Decreased appetite ^† 1	114/405 (28.15%)	149	61/202 (30.20%)	79
Hyperglycaemia ^† 1	27/405 (6.67%)	45	6/202 (2.97%)	9
Hypokalaemia ^† 1	43/405 (10.62%)	70	14/202 (6.93%)	17
Hypomagnesaemia ^† 1	31/405 (7.65%)	43	8/202 (3.96%)	13
Hypophosphataemia ^† 1	21/405 (5.19%)	29	5/202 (2.48%)	7
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	33/405 (8.15%)	43	17/202 (8.42%)	20
Back pain ^† 1	52/405 (12.84%)	61	22/202 (10.89%)	23
Musculoskeletal pain ^† 1	25/405 (6.17%)	32	17/202 (8.42%)	19
Pain in extremity ^† 1	29/405 (7.16%)	32	17/202 (8.42%)	17
Nervous system disorders
Dizziness ^† 1	45/405 (11.11%)	48	18/202 (8.91%)	19
Dysgeusia ^† 1	46/405 (11.36%)	52	19/202 (9.41%)	20
Headache ^† 1	48/405 (11.85%)	57	19/202 (9.41%)	23
Paraesthesia ^† 1	20/405 (4.94%)	27	12/202 (5.94%)	18
Psychiatric disorders
Insomnia ^† 1	24/405 (5.93%)	29	14/202 (6.93%)	14
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	87/405 (21.48%)	112	57/202 (28.22%)	63
Dyspnoea ^† 1	82/405 (20.25%)	98	47/202 (23.27%)	57
Epistaxis ^† 1	29/405 (7.16%)	35	7/202 (3.47%)	11
Haemoptysis ^† 1	11/405 (2.72%)	13	14/202 (6.93%)	15
Oropharyngeal pain ^† 1	21/405 (5.19%)	24	4/202 (1.98%)	4
Productive cough ^† 1	21/405 (5.19%)	24	11/202 (5.45%)	12
Rhinorrhoea ^† 1	22/405 (5.43%)	24	9/202 (4.46%)	9
Skin and subcutaneous tissue disorders
Alopecia ^† 1	21/405 (5.19%)	22	9/202 (4.46%)	9
Dry skin ^† 1	18/405 (4.44%)	19	18/202 (8.91%)	18
Erythema ^† 1	21/405 (5.19%)	24	4/202 (1.98%)	5
Pruritus ^† 1	43/405 (10.62%)	55	21/202 (10.40%)	22
Rash ^† 1	81/405 (20.00%)	108	23/202 (11.39%)	28
1 Term from vocabulary, MedDRA 20.1 † 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 trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

Results Point of Contact

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

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

Garon EB, Aerts J, Kim JS, Muehlenbein CE, Peterson P, Rizzo MT, Gadgeel SM. Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Lung Cancer. 2021 May;155:53-60. doi: 10.1016/j.lungcan.2021.02.021. Epub 2021 Feb 19. Erratum In: Lung Cancer. 2023 Sep;183:107285.

Gadgeel S, Rodriguez-Abreu D, Speranza G, Esteban E, Felip E, Domine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. doi: 10.1200/JCO.19.03136. Epub 2020 Mar 9.

Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodriguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. doi: 10.1016/S1470-2045(19)30801-0. Epub 2020 Feb 6.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT02578680
Other Study ID Numbers:	3475-189 163421 ( Registry Identifier: JAPIC-CTI ) MK-3475-189 ( Other Identifier: Merck Protocol Number ) 2015-003694-15 ( EudraCT Number )
First Submitted:	October 15, 2015
First Posted:	October 19, 2015
Results First Submitted:	September 11, 2018
Results First Posted:	November 28, 2018
Last Update Posted:	July 20, 2023

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