Study of Pembrolizumab (MK-3475) Versus Platinum-Based Chemotherapy for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Advanced or Metastatic Non-Small Cell Lung Cancer (MK-3475-042/KEYNOTE-042)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02220894

Recruitment Status : Completed

First Posted : August 20, 2014

Results First Posted : March 15, 2019

Last Update Posted : October 10, 2023

View this study on the modernized ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Merck Sharp & Dohme LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Non-small Cell Lung Cancer
Interventions	Biological: pembrolizumab Drug: carboplatin Drug: paclitaxel Drug: pemetrexed
Enrollment	1274

Participant Flow

Recruitment Details

Of the 1275 participants randomized (pembrolizumab=638, chemotherapy=637), 1 participant assigned to receive pembrolizumab died prior to randomization and was randomized in error. The intent to treat population was defined as participants alive at the time of randomization, so the actual randomized population included 637 participants in each arm.

Pre-assignment Details

Pembrolizumab-treated participants, who attained a confirmed complete response (CR) or who stopped trial treatment after 35 administrations of study medication for reasons other than disease progression or intolerability, could consider stopping trial treatment. These participants may have been eligible for re-treatment with pembrolizumab monotherapy after they had experienced radiographic disease as per protocol-defined criteria.


Arm/Group Title	Pembrolizumab	Chemotherapy (Standard of Care [SOC] Treatment)
Arm/Group Description	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description	Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 every 3 weeks (Q3W) for a maximum of 35 cycles (21-day cycles). Some participants may have been eligible for re-treatment with pembrolizumab monotherapy after they had experienced radiographic disease as per protocol-defined criteria.	Participants received carboplatin at target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Period Title: Overall Study
Started	637 ^[1]	637
Treated	636	615
Completed	0	0
Not Completed	637	637
Reason Not Completed
Adverse Event	127	74
Death	418	508
Lost to Follow-up	0	4
Site Terminated by Sponsor	2	0
Participation in Study Terminated by Sponsor	80	41
Withdrawal by Parent/Guardian	0	1
Withdrawal by Subject	10	9
[1] 1 additional participant was randomized in error

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Chemotherapy (SOC Treatment)	Total
Arm/Group Description		Participants received pembrolizumab...	Participants received carboplatin a...	Total of all reporting groups
Arm/Group Description		Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W	Total of all reporting groups
Overall Number of Baseline Participants		637	637	1274
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The Baseline Analysis Population consisted of all randomized participants who were alive at the time of randomization and had a Tumor Proportion Score (TPS) ≥1%.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	637 participants	637 participants	1274 participants
		62.5 (9.9)	63.1 (9.4)	62.8 (9.7)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	637 participants	637 participants	1274 participants
	Female	187 29.4%	185 29.0%	372 29.2%
	Male	450 70.6%	452 71.0%	902 70.8%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	637 participants	637 participants	1274 participants
	American Indian or Alaska Native	10 1.6%	5 0.8%	15 1.2%
	Asian	189 29.7%	187 29.4%	376 29.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 0.2%	1 0.1%
	Black or African American	10 1.6%	13 2.0%	23 1.8%
	White	398 62.5%	412 64.7%	810 63.6%
	More than one race	30 4.7%	19 3.0%	49 3.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	637 participants	637 participants	1274 participants
	ECOG PS=0	197 30.9%	192 30.1%	389 30.5%
	ECOG PS=1	439 68.9%	445 69.9%	884 69.4%
	ECOG PS=2	1 0.2%	0 0.0%	1 0.1%
		[1] Measure Description: Participants were assessed for ECOG PS: Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature; Grade 2: Ambulatory & capable of all selfcare but unable to carry out any work activities, up & about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled, cannot carry on any selfcare, totally confined to bed or chair or Grade 5: Dead.
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	637 participants	637 participants	1274 participants
	TPS=≥50%	299 46.9%	300 47.1%	599 47.0%
	TPS=20-49%	114 17.9%	105 16.5%	219 17.2%
	TPS=1-19%	224 35.2%	232 36.4%	456 35.8%
	TPS=<1%	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Description: Participants were assessed for their PD-L1 tumor expression status by immunohistochemistry assay using tumor tissue from an archival or newly obtained biopsy. Participants with a tumor proportion score (TPS) were classified as follows: ≥50% = PD-L1 strongly positive; 1-49% = PD-L1 weakly positive; and <1% = PD-L1 negative.
Tumor Histology ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	637 participants	637 participants	1274 participants
	Squamous	242 38.0%	249 39.1%	491 38.5%
	Non-squamous	395 62.0%	388 60.9%	783 61.5%
		[1] Measure Description: Participants were classified according to tumor histology: Squamous or Non-squamous. The tumor histology determined potential treatment regimen.

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥50%
Description	OS was determined for participants with a TPS of ≥50% and was de...
Description	OS was determined for participants with a TPS of ≥50% and 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 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥50% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	299	300
Median (95% Confidence Interval) Unit of Measure: Months
	20.0 (15.9 to 24.2)	12.2 (10.4 to 14.6)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0003
	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% 0.58 to 0.86
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), and histology (squamous vs. non-squamous).

2.Primary Outcome


Title	Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥20%
Description	OS was determined for participants with a TPS of ≥20% and was de...
Description	OS was determined for participants with a TPS of ≥20% and 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 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥20% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	413	405
Median (95% Confidence Interval) Unit of Measure: Months
	18.0 (15.4 to 21.9)	13.0 (11.6 to 15.3)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0012
	Comments	One-sided p-value based on stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.65 to 0.91
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

3.Primary Outcome


Title	Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥1%
Description	OS was determined for participants with a TPS of ≥1% and was def...
Description	OS was determined for participants with a TPS of ≥1% and 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 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥1% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	637	637
Median (95% Confidence Interval) Unit of Measure: Months
	16.4 (14.0 to 19.7)	12.1 (11.3 to 13.3)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0013
	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	0.82
	Confidence Interval	(2-Sided) 95% 0.71 to 0.93
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

4.Secondary Outcome


Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥50%
Description	PFS was determined for participants with a TPS of ≥50% and was d...
Description	PFS was determined for participants with a TPS of ≥50% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥50% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	299	300
Median (95% Confidence Interval) Unit of Measure: Months
	6.5 (5.9 to 8.5)	6.4 (6.2 to 7.2)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0260
	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	0.83
	Confidence Interval	(2-Sided) 95% 0.69 to 1.00
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).

5.Secondary Outcome


Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥20%
Description	PFS was determined for participants with a TPS of ≥20% and was d...
Description	PFS was determined for participants with a TPS of ≥20% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥20% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	413	405
Median (95% Confidence Interval) Unit of Measure: Months
	6.2 (5.1 to 7.4)	6.7 (6.3 to 8.0)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.2134
	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	0.94
	Confidence Interval	(2-Sided) 95% 0.80 to 1.10
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

6.Secondary Outcome


Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥1%
Description	PFS was determined for participants with a TPS of ≥1% and was de...
Description	PFS was determined for participants with a TPS of ≥1% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥1% is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	637	637
Median (95% Confidence Interval) Unit of Measure: Months
	5.4 (4.3 to 6.2)	6.6 (6.3 to 7.3)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.7964
	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	1.05
	Confidence Interval	(2-Sided) 95% 0.93 to 1.19
	Estimation Comments	Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

7.Secondary Outcome


Title	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥50%
Description	ORR was determined for participants with a TPS of ≥50%. ORR was ...
Description	ORR was determined for participants with a TPS of ≥50%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥50% and who experienced a CR or PR is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	299	300
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	39.1 (33.6 to 44.9)	32.0 (26.8 to 37.6)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0353
	Comments	One-sided p-value for testing. 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 (DP)
	Estimated Value	7.0
	Confidence Interval	(2-Sided) 95% -0.6 to 14.6
	Estimation Comments	DP for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. nonsquamous).

8.Secondary Outcome


Title	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥20%
Description	ORR was determined for participants with a TPS of ≥20%. ORR was ...
Description	ORR was determined for participants with a TPS of ≥20%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥20% and who experienced a CR or PR is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	413	405
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	33.2 (28.6 to 37.9)	28.9 (24.5 to 33.6)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.0744
	Comments	One-sided p-value for testing. 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 (DP)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95% -1.7 to 10.9
	Estimation Comments	DP for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

9.Secondary Outcome


Title	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥1%
Description	ORR was determined for participants with a TPS of ≥1%. ORR was d...
Description	ORR was determined for participants with a TPS of ≥1%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥1% and who experienced a CR or PR is presented.
Time Frame	Up to approximately 44 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	637	637
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	27.2 (23.7 to 30.8)	26.5 (23.1 to 30.1)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.4060
	Comments	One-sided p-value for testing. 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 (DP)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95% -4.2 to 5.4
	Estimation Comments	DP for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).

10.Secondary Outcome


Title	Number of Participants Who Experienced At Least One Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant ...
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented.
Time Frame	Up to approximately 38 months

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	636	615
Measure Type: Count of Participants Unit of Measure: Participants
	608 95.6%	606 98.5%

11.Secondary Outcome


Title	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant ...
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Time Frame	Up to approximately 35 months

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Pembrolizumab	Chemotherapy (SOC Treatment)
Arm/Group Description:	Participants received pembrolizumab...	Participants received carboplatin a...
Arm/Group Description:	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)	Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
Overall Number of Participants Analyzed	636	615
Measure Type: Count of Participants Unit of Measure: Participants
	126 19.8%	93 15.1%

Adverse Events

Time Frame	Up to approximately 93 months
Adverse Event Reporting Description	Population: All participants receiving ≥1 dose of study treatment. 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.

Arm/Group Title	Pembrolizumab		Chemotherapy (SOC Treatment)		Pembrolizumab Second Course
Arm/Group Description	Participants received pembrolizumab...		Participants received carboplatin a...		Eligible participants who stopped t...
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)		Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W.		Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
All-Cause Mortality
	Pembrolizumab		Chemotherapy (SOC Treatment)		Pembrolizumab Second Course
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	528/637 (82.89%)		582/637 (91.37%)		18/34 (52.94%)
Serious Adverse Events Serious Adverse Events
	Pembrolizumab		Chemotherapy (SOC Treatment)		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	261/636 (41.04%)		193/615 (31.38%)		8/34 (23.53%)
Blood and lymphatic system disorders
Agranulocytosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Anaemia ^† 1	3/636 (0.47%)	3	16/615 (2.60%)	23	0/34 (0.00%)	0
Lymphadenopathy ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Neutropenia ^† 1	0/636 (0.00%)	0	8/615 (1.30%)	8	0/34 (0.00%)	0
Thrombocytopenia ^† 1	1/636 (0.16%)	1	6/615 (0.98%)	6	0/34 (0.00%)	0
Febrile neutropenia ^† 1	1/636 (0.16%)	1	16/615 (2.60%)	17	0/34 (0.00%)	0
Leukopenia ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Normochromic anaemia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Splenic infarction ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Cardiac disorders
Coronary artery disease ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Myocardial infarction ^† 1	3/636 (0.47%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Acute coronary syndrome ^† 1	0/636 (0.00%)	0	3/615 (0.49%)	3	0/34 (0.00%)	0
Acute myocardial infarction ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Aortic valve stenosis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Arrhythmia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Atrial fibrillation ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Atrial flutter ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Cardiac arrest ^† 1	3/636 (0.47%)	3	1/615 (0.16%)	1	0/34 (0.00%)	0
Cardiac failure ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Cardiac failure acute ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Cardiac tamponade ^† 1	3/636 (0.47%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Cardio-respiratory arrest ^† 1	3/636 (0.47%)	3	1/615 (0.16%)	1	0/34 (0.00%)	0
Cardiopulmonary failure ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Myocarditis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pericardial effusion ^† 1	6/636 (0.94%)	6	0/615 (0.00%)	0	0/34 (0.00%)	0
Pericarditis ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Sinus tachycardia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Supraventricular tachycardia ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Ventricular fibrillation ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Ear and labyrinth disorders
Vertigo ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Endocrine disorders
Adrenal insufficiency ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Hyperthyroidism ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hypophysitis ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Hypopituitarism ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hypothyroidism ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastrointestinal disorders
Diarrhoea ^† 1	5/636 (0.79%)	5	3/615 (0.49%)	3	1/34 (2.94%)	1
Abdominal pain ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Colitis ^† 1	6/636 (0.94%)	6	0/615 (0.00%)	0	0/34 (0.00%)	0
Constipation ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Duodenal perforation ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Dyspepsia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Enterocolitis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Gastric haemorrhage ^† 1	1/636 (0.16%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastric ulcer haemorrhage ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastritis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Gastrointestinal ulcer ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Glossitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Haematemesis ^† 1	0/636 (0.00%)	0	0/615 (0.00%)	0	1/34 (2.94%)	1
Ileus paralytic ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Incarcerated inguinal hernia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Inguinal hernia ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Intestinal ischaemia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Melaena ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Nausea ^† 1	3/636 (0.47%)	3	2/615 (0.33%)	2	0/34 (0.00%)	0
Neutropenic colitis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Oesophageal fistula ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pancreatic mass ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Rectal ulcer ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Stomatitis ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Upper gastrointestinal haemorrhage ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	2	1/34 (2.94%)	1
Volvulus ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Vomiting ^† 1	2/636 (0.31%)	2	2/615 (0.33%)	2	0/34 (0.00%)	0
General disorders
Death ^† 1	9/636 (1.42%)	9	5/615 (0.81%)	5	0/34 (0.00%)	0
Fatigue ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Malaise ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Pyrexia ^† 1	4/636 (0.63%)	4	0/615 (0.00%)	0	1/34 (2.94%)	1
Accidental death ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Asthenia ^† 1	1/636 (0.16%)	1	4/615 (0.65%)	4	0/34 (0.00%)	0
General physical health deterioration ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Ill-defined disorder ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Performance status decreased ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Prosthetic cardiac valve thrombosis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Sudden death ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	3/636 (0.47%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Hepatic function abnormal ^† 1	2/636 (0.31%)	2	1/615 (0.16%)	1	0/34 (0.00%)	0
Hepatitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hepatitis acute ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hepatitis toxic ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Immune-mediated hepatitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Immune system disorders
Anaphylactic reaction ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Contrast media allergy ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infections and infestations
Infection ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Lung abscess ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Pneumonia ^† 1	49/636 (7.70%)	54	34/615 (5.53%)	41	2/34 (5.88%)	2
Septic shock ^† 1	3/636 (0.47%)	3	4/615 (0.65%)	4	0/34 (0.00%)	0
Upper respiratory tract infection ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Lymph gland infection ^† 1	0/636 (0.00%)	0	0/615 (0.00%)	0	1/34 (2.94%)	1
Abdominal sepsis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Abscess jaw ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Amoebiasis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Amoebic dysentery ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Anal abscess ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Biliary sepsis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Bronchitis ^† 1	8/636 (1.26%)	8	3/615 (0.49%)	3	0/34 (0.00%)	0
COVID-19 ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Candida infection ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Cellulitis ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	3	0/34 (0.00%)	0
Clostridium difficile infection ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Cystitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Device related infection ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Diverticulitis ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Enterocolitis infectious ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Gastroenteritis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastroenteritis viral ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Herpes zoster ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infectious pleural effusion ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infective exacerbation of bronchiectasis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Influenza ^† 1	2/636 (0.31%)	2	2/615 (0.33%)	2	0/34 (0.00%)	0
Laryngitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Lower respiratory tract infection ^† 1	0/636 (0.00%)	0	3/615 (0.49%)	3	0/34 (0.00%)	0
Neutropenic sepsis ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Oesophageal candidiasis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Peritonitis ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Pleural infection ^† 1	1/636 (0.16%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Pneumocystis jirovecii pneumonia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Pneumonia aspiration ^† 1	2/636 (0.31%)	2	1/615 (0.16%)	1	0/34 (0.00%)	0
Pneumonia bacterial ^† 1	3/636 (0.47%)	3	2/615 (0.33%)	2	1/34 (2.94%)	1
Pneumonia klebsiella ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Post procedural cellulitis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pseudomembranous colitis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Pulmonary sepsis ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Respiratory tract infection ^† 1	2/636 (0.31%)	2	1/615 (0.16%)	1	0/34 (0.00%)	0
Sepsis ^† 1	4/636 (0.63%)	4	3/615 (0.49%)	4	0/34 (0.00%)	0
Urinary tract infection ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Vascular access site infection ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Viral infection ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Injury, poisoning and procedural complications
Subdural haematoma ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Cervical vertebral fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Femur fracture ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Hip fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infusion related reaction ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Lumbar vertebral fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Radius fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Subdural haemorrhage ^† 1	0/636 (0.00%)	0	0/615 (0.00%)	0	1/34 (2.94%)	1
Upper limb fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Investigations
Neutrophil count decreased ^† 1	0/636 (0.00%)	0	5/615 (0.81%)	5	0/34 (0.00%)	0
Platelet count decreased ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	3	0/34 (0.00%)	0
Alanine aminotransferase increased ^† 1	3/636 (0.47%)	3	2/615 (0.33%)	2	0/34 (0.00%)	0
Aspartate aminotransferase increased ^† 1	3/636 (0.47%)	3	1/615 (0.16%)	1	0/34 (0.00%)	0
Bilirubin conjugated increased ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Blood bilirubin increased ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Blood calcium decreased ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Blood pressure increased ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Blood prolactin increased ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	4/636 (0.63%)	4	3/615 (0.49%)	3	0/34 (0.00%)	0
Diabetes mellitus ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Electrolyte imbalance ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Hyperuricaemia ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	3	0/34 (0.00%)	0
Hyponatraemia ^† 1	3/636 (0.47%)	3	1/615 (0.16%)	1	0/34 (0.00%)	0
Ketoacidosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Dehydration ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Hypercalcaemia ^† 1	2/636 (0.31%)	2	2/615 (0.33%)	2	0/34 (0.00%)	0
Hyperkalaemia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hypoglycaemia ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Type 2 diabetes mellitus ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Musculoskeletal and connective tissue disorders
Bone pain ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Neck pain ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Arthralgia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Back pain ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Musculoskeletal chest pain ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Myalgia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Osteitis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Osteoporotic fracture ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pain in extremity ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Rotator cuff syndrome ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Metastases to bone ^† 1	2/636 (0.31%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Oesophageal carcinoma ^† 1	3/636 (0.47%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Adenocarcinoma gastric ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Anogenital warts ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Cancer pain ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Gastric cancer ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Infected neoplasm ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Keratoacanthoma ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Lung cancer metastatic ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Lung neoplasm malignant ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Squamous cell carcinoma ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Squamous cell carcinoma of the tongue ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Tumour associated fever ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	1/34 (2.94%)	1
Tumour necrosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Nervous system disorders
Cerebral infarction ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Dizziness ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Haemorrhage intracranial ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Altered state of consciousness ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Ataxia ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Cerebral ischaemia ^† 1	3/636 (0.47%)	3	0/615 (0.00%)	0	0/34 (0.00%)	0
Cerebrovascular accident ^† 1	2/636 (0.31%)	2	3/615 (0.49%)	3	0/34 (0.00%)	0
Coma ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Embolic stroke ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Encephalopathy ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Epilepsy ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Headache ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Ischaemic stroke ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Loss of consciousness ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Metabolic encephalopathy ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Neuropathy peripheral ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Psychomotor hyperactivity ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Seizure ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	3	0/34 (0.00%)	0
Spinal cord compression ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Syncope ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Transient ischaemic attack ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Psychiatric disorders
Completed suicide ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Confusional state ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Delirium ^† 1	2/636 (0.31%)	2	2/615 (0.33%)	2	0/34 (0.00%)	0
Depression ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Renal and urinary disorders
Renal failure ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Acute kidney injury ^† 1	3/636 (0.47%)	3	4/615 (0.65%)	4	0/34 (0.00%)	0
Glomerulonephritis membranous ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Hydronephrosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Nephritis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Nephropathy ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Renal tubular necrosis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Urinary retention ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Ovarian cyst torsion ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	2/636 (0.31%)	2	5/615 (0.81%)	5	0/34 (0.00%)	0
Haemoptysis ^† 1	7/636 (1.10%)	7	1/615 (0.16%)	1	0/34 (0.00%)	0
Interstitial lung disease ^† 1	4/636 (0.63%)	6	1/615 (0.16%)	1	0/34 (0.00%)	0
Pleural effusion ^† 1	14/636 (2.20%)	16	5/615 (0.81%)	7	0/34 (0.00%)	0
Pulmonary embolism ^† 1	13/636 (2.04%)	13	11/615 (1.79%)	11	0/34 (0.00%)	0
Respiratory failure ^† 1	4/636 (0.63%)	4	4/615 (0.65%)	4	0/34 (0.00%)	0
Acute pulmonary oedema ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Acute respiratory failure ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Asthma ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Atelectasis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Bronchitis chronic ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Chronic respiratory failure ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Dyspnoea ^† 1	7/636 (1.10%)	8	1/615 (0.16%)	1	0/34 (0.00%)	0
Hydrothorax ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Lung disorder ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Oesophagobronchial fistula ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Pleurisy ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pneumonitis ^† 1	25/636 (3.93%)	26	1/615 (0.16%)	1	0/34 (0.00%)	0
Pneumothorax ^† 1	3/636 (0.47%)	3	1/615 (0.16%)	1	0/34 (0.00%)	0
Pulmonary artery thrombosis ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Pulmonary fistula ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Pulmonary haemorrhage ^† 1	4/636 (0.63%)	4	2/615 (0.33%)	2	0/34 (0.00%)	0
Pulmonary oedema ^† 1	1/636 (0.16%)	1	2/615 (0.33%)	2	0/34 (0.00%)	0
Pulmonary thrombosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Respiratory distress ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
Tracheal stenosis ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Skin and subcutaneous tissue disorders
Drug eruption ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	2	0/34 (0.00%)	0
Urticaria ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Rash ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	1/34 (2.94%)	1
Rash maculo-papular ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Vascular disorders
Hypertension ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Superior vena cava syndrome ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Aortic aneurysm ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Arterial thrombosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Deep vein thrombosis ^† 1	1/636 (0.16%)	1	1/615 (0.16%)	1	0/34 (0.00%)	0
Embolism ^† 1	2/636 (0.31%)	2	0/615 (0.00%)	0	0/34 (0.00%)	0
Hypotension ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Jugular vein thrombosis ^† 1	0/636 (0.00%)	0	1/615 (0.16%)	1	0/34 (0.00%)	0
Peripheral artery occlusion ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Peripheral ischaemia ^† 1	1/636 (0.16%)	1	0/615 (0.00%)	0	0/34 (0.00%)	0
Venous thrombosis ^† 1	0/636 (0.00%)	0	2/615 (0.33%)	2	0/34 (0.00%)	0
1 Term from vocabulary, MedDRA 25.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab		Chemotherapy (SOC Treatment)		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	535/636 (84.12%)		577/615 (93.82%)		21/34 (61.76%)
Blood and lymphatic system disorders
Anaemia ^† 1	102/636 (16.04%)	124	253/615 (41.14%)	332	2/34 (5.88%)	2
Leukopenia ^† 1	10/636 (1.57%)	17	35/615 (5.69%)	63	1/34 (2.94%)	1
Neutropenia ^† 1	6/636 (0.94%)	9	85/615 (13.82%)	177	0/34 (0.00%)	0
Thrombocytopenia ^† 1	6/636 (0.94%)	7	59/615 (9.59%)	86	0/34 (0.00%)	0
Endocrine disorders
Hyperthyroidism ^† 1	37/636 (5.82%)	38	4/615 (0.65%)	4	1/34 (2.94%)	1
Hypothyroidism ^† 1	76/636 (11.95%)	99	10/615 (1.63%)	10	3/34 (8.82%)	5
Gastrointestinal disorders
Constipation ^† 1	78/636 (12.26%)	98	131/615 (21.30%)	168	3/34 (8.82%)	3
Diarrhoea ^† 1	74/636 (11.64%)	94	78/615 (12.68%)	107	3/34 (8.82%)	5
Nausea ^† 1	73/636 (11.48%)	98	195/615 (31.71%)	407	1/34 (2.94%)	1
Vomiting ^† 1	50/636 (7.86%)	62	106/615 (17.24%)	167	0/34 (0.00%)	0
Stomatitis ^† 1	16/636 (2.52%)	18	33/615 (5.37%)	40	0/34 (0.00%)	0
General disorders
Asthenia ^† 1	69/636 (10.85%)	92	81/615 (13.17%)	110	2/34 (5.88%)	3
Chest pain ^† 1	56/636 (8.81%)	61	43/615 (6.99%)	52	1/34 (2.94%)	1
Fatigue ^† 1	101/636 (15.88%)	129	129/615 (20.98%)	193	0/34 (0.00%)	0
Malaise ^† 1	15/636 (2.36%)	15	32/615 (5.20%)	49	1/34 (2.94%)	1
Pyrexia ^† 1	64/636 (10.06%)	82	52/615 (8.46%)	63	1/34 (2.94%)	1
Oedema peripheral ^† 1	32/636 (5.03%)	33	36/615 (5.85%)	50	1/34 (2.94%)	1
Infections and infestations
Pneumonia ^† 1	39/636 (6.13%)	40	30/615 (4.88%)	35	1/34 (2.94%)	1
Upper respiratory tract infection ^† 1	46/636 (7.23%)	62	32/615 (5.20%)	41	1/34 (2.94%)	1
Nasopharyngitis ^† 1	26/636 (4.09%)	37	21/615 (3.41%)	26	3/34 (8.82%)	4
Bronchitis ^† 1	30/636 (4.72%)	34	23/615 (3.74%)	25	3/34 (8.82%)	4
Investigations
Alanine aminotransferase increased ^† 1	66/636 (10.38%)	89	72/615 (11.71%)	97	3/34 (8.82%)	4
Aspartate aminotransferase increased ^† 1	62/636 (9.75%)	83	57/615 (9.27%)	87	3/34 (8.82%)	3
Neutrophil count decreased ^† 1	6/636 (0.94%)	6	89/615 (14.47%)	239	0/34 (0.00%)	0
Platelet count decreased ^† 1	7/636 (1.10%)	7	65/615 (10.57%)	144	0/34 (0.00%)	0
Weight decreased ^† 1	67/636 (10.53%)	71	48/615 (7.80%)	49	4/34 (11.76%)	4
White blood cell count decreased ^† 1	5/636 (0.79%)	7	77/615 (12.52%)	228	1/34 (2.94%)	1
Blood alkaline phosphatase increased ^† 1	39/636 (6.13%)	46	30/615 (4.88%)	35	2/34 (5.88%)	2
Metabolism and nutrition disorders
Decreased appetite ^† 1	108/636 (16.98%)	127	134/615 (21.79%)	209	3/34 (8.82%)	3
Hyperglycaemia ^† 1	21/636 (3.30%)	26	32/615 (5.20%)	43	1/34 (2.94%)	1
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	86/636 (13.52%)	109	87/615 (14.15%)	162	3/34 (8.82%)	3
Back pain ^† 1	61/636 (9.59%)	70	43/615 (6.99%)	51	1/34 (2.94%)	1
Myalgia ^† 1	32/636 (5.03%)	37	70/615 (11.38%)	135	1/34 (2.94%)	1
Pain in extremity ^† 1	31/636 (4.87%)	36	34/615 (5.53%)	40	0/34 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	25/636 (3.93%)	28	39/615 (6.34%)	49	0/34 (0.00%)	0
Headache ^† 1	44/636 (6.92%)	58	51/615 (8.29%)	62	2/34 (5.88%)	2
Neuropathy peripheral ^† 1	5/636 (0.79%)	6	52/615 (8.46%)	62	0/34 (0.00%)	0
Peripheral sensory neuropathy ^† 1	4/636 (0.63%)	5	43/615 (6.99%)	55	0/34 (0.00%)	0
Psychiatric disorders
Insomnia ^† 1	34/636 (5.35%)	38	45/615 (7.32%)	51	0/34 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	107/636 (16.82%)	128	66/615 (10.73%)	72	2/34 (5.88%)	2
Dyspnoea ^† 1	105/636 (16.51%)	120	72/615 (11.71%)	81	1/34 (2.94%)	1
Haemoptysis ^† 1	45/636 (7.08%)	62	23/615 (3.74%)	25	3/34 (8.82%)	4
Skin and subcutaneous tissue disorders
Alopecia ^† 1	3/636 (0.47%)	4	138/615 (22.44%)	139	0/34 (0.00%)	0
Pruritus ^† 1	67/636 (10.53%)	83	22/615 (3.58%)	23	2/34 (5.88%)	4
Rash ^† 1	72/636 (11.32%)	82	43/615 (6.99%)	52	1/34 (2.94%)	4
Vascular disorders
Hypertension ^† 1	41/636 (6.45%)	49	14/615 (2.28%)	17	1/34 (2.94%)	1
1 Term from vocabulary, MedDRA 25.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. 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 LLC
Phone:	1-800-672-6372
EMail:	ClinicalTrialsDisclosure@merck.com

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

de Castro G Jr, Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score >/= 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. doi: 10.1200/JCO.21.02885. Epub 2022 Oct 28.

Halmos B, Burke T, Kalyvas C, Insinga R, Vandormael K, Frederickson A, Piperdi B. Indirect comparison of pembrolizumab monotherapy versus nivolumab + ipilimumab in first-line metastatic lung cancer. Immunotherapy. 2022 Apr;14(5):295-307. doi: 10.2217/imt-2021-0273. Epub 2022 Jan 25.

Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, Zhou C, Dang T, Sadowski S, Kush DA, Zhou Y, Li B, Mok T. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int J Cancer. 2021 May 1;148(9):2313-2320. doi: 10.1002/ijc.33399. Epub 2020 Dec 9.

Weng X, Luo S, Lin S, Zhong L, Li M, Xin R, Huang P, Xu X. Cost-Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels. Oncol Res. 2020 Mar 27;28(2):117-125. doi: 10.3727/096504019X15707883083132. Epub 2019 Oct 14.

Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT02220894
Other Study ID Numbers:	3475-042 152877 ( Registry Identifier: JAPIC-CTI ) MK-3475-042 ( Other Identifier: Merck Protocol Number ) KEYNOTE-042 ( Other Identifier: Merck ) 2014-001473-14 ( EudraCT Number )
First Submitted:	August 19, 2014
First Posted:	August 20, 2014
Results First Submitted:	February 14, 2019
Results First Posted:	March 15, 2019
Last Update Posted:	October 10, 2023

To Top