A Study of Pembrolizumab (MK-3475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for Participants With Extensive Stage Small Cell Lung Cancer (MK-3475-604/KEYNOTE-604)

• ClinicalTrials.gov Identifier: NCT03066778
• Recruitment Status: Completed
• First Posted: February 28, 2017
• Results First Posted: December 22, 2020
• Last Update Posted: October 3, 2022
• Sponsor: Merck Sharp & Dohme LLC
• 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: Small Cell Lung Cancer (SCLC)
• Interventions: Biological: Pembrolizumab; Drug: Normal saline solution; Drug: Carboplatin; Drug: Cisplatin; Drug: Etoposide
• Enrollment: 453

Participant Flow

Recruitment Details

Participants in the pembrolizumab+ chemotherapy (etoposide/platinum [EP]) arm were eligible to receive second course treatment with pembrolizumab if they met criteria for re-treatment. Per protocol, response, progression, or patient reported outcomes during the second course were not counted towards efficacy outcome measures and adverse events during the second course were not counted towards safety outcome measures.

Pre-assignment Details

One participant who was randomized to the pembrolizumab+EP arm was inadvertently treated with placebo+EP. For efficacy analyses this participant will be included in the arm they were initially randomized into and for safety analyses the participant will be included by treatment received.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Period Title: Overall Study
Started	228	225
Treated	223 [1]	223
Received Second Course of Pembrolizumab	1	0
Completed	28	13
Not Completed	200	212
Reason Not Completed
Death	195	205
Withdrawal by Subject	5	7
[1] 1 participant randomized to the pembrolizumab+EP arm was treated with placebo+EP.

Baseline Characteristics

Arm/Group Title		Pembrolizumab+EP	Placebo+EP	Total
Arm/Group Description		During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).	Total of all reporting groups
Overall Number of Baseline Participants		228	225	453
Baseline Analysis Population Description		All participants randomized by intention to treat (ITT).
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	228 participants	225 participants	453 participants
		64.2 (8.4)	65.2 (8.2)	64.7 (8.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	228 participants	225 participants	453 participants
	Female	76 33.3%	83 36.9%	159 35.1%
	Male	152 66.7%	142 63.1%	294 64.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	228 participants	225 participants	453 participants
	Hispanic or Latino	6 2.6%	13 5.8%	19 4.2%
	Not Hispanic or Latino	204 89.5%	192 85.3%	396 87.4%
	Unknown or Not Reported	18 7.9%	20 8.9%	38 8.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	228 participants	225 participants	453 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	52 22.8%	34 15.1%	86 19.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 0.4%	0 0.0%	1 0.2%
	White	162 71.1%	177 78.7%	339 74.8%
	More than one race	0 0.0%	1 0.4%	1 0.2%
	Unknown or Not Reported	13 5.7%	13 5.8%	26 5.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	228 participants	225 participants	453 participants
ECOG = 0		60 26.3%	56 24.9%	116 25.6%
ECOG = 1		168 73.7%	169 75.1%	337 74.4%
		[1] Measure Description: An ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) was required for inclusion in the study and randomization was stratified by ECOG score.
Lactate Dehydrogenase (LDH) Status at Baseline [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	228 participants	225 participants	453 participants
LDH = ≤ Upper Limit of Normal		100 43.9%	95 42.2%	195 43.0%
LDH = > Upper Limit of Normal		127 55.7%	129 57.3%	256 56.5%
LDH Result Missing		1 0.4%	1 0.4%	2 0.4%
		[1] Measure Description: Randomization of participants in the study was stratified by LDH measurement at baseline ( ≤ or > upper limit of normal).
Platinum Therapy Administered [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	228 participants	225 participants	453 participants
Cisplatin		63 27.6%	66 29.3%	129 28.5%
Carboplatin		161 70.6%	156 69.3%	317 70.0%
Not Treated with Platinum Therapy		4 1.8%	3 1.3%	7 1.5%
		[1] Measure Description: Randomization of participants was stratified by type of platinum therapy administered during the study.

Outcome Measures

1. Primary 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)
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. PD, as determined by RECIST 1.1, 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. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The PFS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	228	225
Median (95% Confidence Interval); Unit of Measure: Months
	4.8; (4.3 to 5.4)	4.3; (4.2 to 4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab+EP, Placebo+EP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00069
	Comments	[Not Specified]
	Method	Log Rank
	Comments	One-sided p-value based on log-rank test stratified by platinum chemotherapy, ECOG, and LDH
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.88
	Estimation Comments	Based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by platinum chemotherapy, ECOG, and LDH

2. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	228	225
Median (95% Confidence Interval); Unit of Measure: Months
	10.8; (9.2 to 12.9)	9.7; (8.6 to 10.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab+EP, Placebo+EP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.01643
	Comments	[Not Specified]
	Method	Log Rank
	Comments	One-sided p-value based on log-rank test stratified by platinum chemotherapy, ECOG, and LDH
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.98
	Estimation Comments	Based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by platinum chemotherapy, ECOG, and LDH

3. 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)
Description	ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or > upper limit of normal) and presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	228	225
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	70.6; (64.2 to 76.4)	61.8; (55.1 to 68.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab+EP, Placebo+EP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.02270
	Comments	[Not Specified]
	Method	Miettinen & Nurminen
	Comments	One-sided p-value for testing. H0: difference in percent = 0 versus H1: difference in percent > 0.
Method of Estimation	Estimation Parameter	Percent Difference
	Estimated Value	8.9
	Confidence Interval	(2-Sided) 95%; 0.2 to 17.4
	Estimation Comments	Based on Miettinen & Nurminen method stratified by platinum chemotherapy, ECOG, and LDH. Cisplatin, ECOG 0, LDH ≤ULN and Cisplatin, ECOG 0, LDH >ULN were combined into one stratum because of small sample size

4. Secondary Outcome

Title	Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
Description	DOR was defined as the time from first documented evidence of a Complete Response (CR) or Partial Response (PR) per RECIST 1.1 until progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurred first. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. 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 ≥1 new lesions was also considered PD. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data and is presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized and experienced a CR or PR.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	161	139
Median (Full Range); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA=median DOR and upper and lower limits not reached due to no progressive disease by time of last disease assessment

5. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	223	223
Measure Type: Count of Participants; Unit of Measure: Participants
	223 100.0%	222 99.6%

6. Secondary Outcome

Title	Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)
Description	An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who discontinued due to an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 26 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	223	223
Measure Type: Count of Participants; Unit of Measure: Participants
	33 14.8%	14 6.3%

7. Secondary Outcome

Title	Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03)
Description	The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time Frame	Up to approximately 30.5 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	223	223
Measure Type: Count of Participants; Unit of Measure: Participants
	175 78.5%	172 77.1%

8. Secondary Outcome

Title	Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
Description	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis (cLDA) model. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Data are presented for the first course of study treatment per protocol.
Time Frame	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 18.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	221	218
Least Squares Mean (95% Confidence Interval); Unit of Measure: Score on a Scale
	8.66; (5.26 to 12.06)	4.23; (0.93 to 7.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab+EP, Placebo+EP
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.040
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Least Square Means
	Estimated Value	4.43
	Confidence Interval	(2-Sided) 95%; 0.21 to 8.66
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
Description	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.
Time Frame	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 12. This outcome measure was replaced with a single time-point analysis at Week 18 as pre-specified with Amendment 7 of the protocol (03-Oct-2018).

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

10. Secondary Outcome

Title	Change From Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
Description	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.
Time Frame	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 24. This outcome measure was replaced with a single time-point analysis at Week 18 as pre-specified with Amendment 7 of the protocol (03-Oct-2018).

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

11. Secondary Outcome

Title	Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13)
Description	TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as the time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy and radiation. It is scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0 to 100 using a standard algorithm. Higher scores represented increasing symptom severity. TTD was calculated using the product-limit Kaplan-Meier method for censored data and is presented for the first course of study treatment per protocol.
Time Frame	Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study medication and had non-missing assessments.

Arm/Group Title	Pembrolizumab+EP	Placebo+EP
Arm/Group Description:	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.	During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
Overall Number of Participants Analyzed	221	218
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	8.7 [2]; (5.9 to NA)

[1]

Median TTD and lower and upper limits not reached (no protocol-specified deterioration criteria reached by time of last assessment)

[2]

TTD upper limit not reached (no protocol-specified deterioration criteria reached by time of last assessment)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab+EP, Placebo+EP
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.208
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Two-sided p-value based on stratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.14
	Estimation Comments	Based on Cox regression model with treatment as a covariate stratified by platinum chemotherapy ECOG, and LDH. Cisplatin, ECOG 0, LDH ≤ULN and Cisplatin, ECOG 0, LDH >ULN were combined into one stratum because of small sample size

Adverse Events

Time Frame	First Course: Up to 49.5 months Second Course: Up to 37.9 months First and second course dosing occurred concurrently
Adverse Event Reporting Description	All-cause mortality (ACM)=all randomized participants; AE=all participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms neoplasm progression (NP), malignant NP, disease progression not related to study treatment are excluded. ACM was adjusted for the participant who was randomized to pembrolizumab+EP and treated with placebo+EP. AEs presented by actual treatment received. Per protocol, collection of AE and ACM were planned for first and second courses.
Arm/Group Title	Pembrolizumab+EP		Placebo+EP		Pembrolizumab Second Course
Arm/Group Description	During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.		During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).		Participants who met the criteria for retreatment received pembrolizumab 200 mg by IV infusion on Day 1 of each 21-day cycle for up to 1 year of treatment.
All-Cause Mortality
	Pembrolizumab+EP		Placebo+EP		Pembrolizumab Second Course
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	196/227 (86.34%)		212/226 (93.81%)		1/1 (100.00%)
Serious Adverse Events
	Pembrolizumab+EP		Placebo+EP		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/223 (49.78%)		89/223 (39.91%)		1/1 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	7/223 (3.14%)	7	10/223 (4.48%)	10	0/1 (0.00%)	0
Febrile neutropenia † 1	15/223 (6.73%)	15	14/223 (6.28%)	14	0/1 (0.00%)	0
Leukopenia † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Neutropenia † 1	11/223 (4.93%)	11	6/223 (2.69%)	6	0/1 (0.00%)	0
Thrombocytopenia † 1	3/223 (1.35%)	3	5/223 (2.24%)	6	0/1 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Atrial fibrillation † 1	4/223 (1.79%)	4	3/223 (1.35%)	3	0/1 (0.00%)	0
Cardiac arrest † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Cardiac failure † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Cardiopulmonary failure † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Myocardial infarction † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Myocarditis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Pericardial effusion † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Endocrine disorders
Hyperthyroidism † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Hypopituitarism † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Inappropriate antidiuretic hormone secretion † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Secondary adrenocortical insufficiency † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Eye disorders
Autoimmune uveitis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Keratitis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Vitreous haemorrhage † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Gastrointestinal disorders
Colitis † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Constipation † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Diarrhoea † 1	3/223 (1.35%)	3	1/223 (0.45%)	1	0/1 (0.00%)	0
Diverticulum † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Food poisoning † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Gastritis † 1	2/223 (0.90%)	2	1/223 (0.45%)	1	0/1 (0.00%)	0
Haematemesis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Nausea † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Oesophagitis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Proctitis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Vomiting † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
General disorders
Asthenia † 1	3/223 (1.35%)	3	1/223 (0.45%)	1	0/1 (0.00%)	0
Chest pain † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Death † 1	4/223 (1.79%)	4	3/223 (1.35%)	3	0/1 (0.00%)	0
Fatigue † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Oedema peripheral † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Pain † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Pyrexia † 1	4/223 (1.79%)	4	2/223 (0.90%)	2	0/1 (0.00%)	0
Hepatobiliary disorders
Cholecystitis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Hepatotoxicity † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Infections and infestations
Appendicitis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Atypical pneumonia † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Bacteraemia † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Bronchitis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Cholecystitis infective † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Clostridium difficile colitis † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Diverticulitis † 1	0/223 (0.00%)	0	1/223 (0.45%)	2	0/1 (0.00%)	0
Empyema † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Escherichia sepsis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Gastroenteritis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Gastrointestinal viral infection † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Herpes zoster † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease † 1	0/223 (0.00%)	0	1/223 (0.45%)	2	0/1 (0.00%)	0
Influenza † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Lower respiratory tract infection † 1	0/223 (0.00%)	0	3/223 (1.35%)	3	0/1 (0.00%)	0
Neutropenic sepsis † 1	3/223 (1.35%)	3	1/223 (0.45%)	1	0/1 (0.00%)	0
Paracancerous pneumonia † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Pleural infection † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Pneumonia † 1	17/223 (7.62%)	20	12/223 (5.38%)	13	0/1 (0.00%)	0
Pneumonia aspiration † 1	0/223 (0.00%)	0	2/223 (0.90%)	2	0/1 (0.00%)	0
Pneumonia haemophilus † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Pseudomonas infection † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Sepsis † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Serratia sepsis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Tooth infection † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Upper respiratory tract infection † 1	0/223 (0.00%)	0	3/223 (1.35%)	3	0/1 (0.00%)	0
Urinary tract infection † 1	3/223 (1.35%)	3	0/223 (0.00%)	0	0/1 (0.00%)	0
Urosepsis † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Femur fracture † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Infusion related reaction † 1	2/223 (0.90%)	2	1/223 (0.45%)	1	0/1 (0.00%)	0
Joint injury † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Skin laceration † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Spinal fracture † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Aspartate aminotransferase increased † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Blood creatinine increased † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Dehydration † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Diabetes mellitus † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Hyperglycaemia † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Hyponatraemia † 1	4/223 (1.79%)	6	5/223 (2.24%)	11	0/1 (0.00%)	0
Type 1 diabetes mellitus † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Back pain † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Gouty arthritis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Myositis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Spinal osteoarthritis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	0/223 (0.00%)	0	2/223 (0.90%)	2	0/1 (0.00%)	0
Colon cancer † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Paraneoplastic syndrome † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Nervous system disorders
Aphasia † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Cerebrovascular accident † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Cognitive disorder † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Dizziness † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Hemiparesis † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Limbic encephalitis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Loss of consciousness † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Parkinsonism † 1	0/223 (0.00%)	0	0/223 (0.00%)	0	1/1 (100.00%)	1
Peripheral motor neuropathy † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Presyncope † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Syncope † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Toxic encephalopathy † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Transient ischaemic attack † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Tremor † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Psychiatric disorders
Confusional state † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	5/223 (2.24%)	7	1/223 (0.45%)	1	0/1 (0.00%)	0
Autoimmune nephritis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Haematuria † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Neurogenic bladder † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Prostatitis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Chronic obstructive pulmonary disease † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Dyspnoea † 1	3/223 (1.35%)	3	1/223 (0.45%)	1	0/1 (0.00%)	0
Epistaxis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Haemoptysis † 1	1/223 (0.45%)	1	2/223 (0.90%)	2	0/1 (0.00%)	0
Hypoxia † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	0/1 (0.00%)	0
Laryngeal haemorrhage † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Oropharyngeal pain † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Pleural effusion † 1	1/223 (0.45%)	1	3/223 (1.35%)	4	0/1 (0.00%)	0
Pneumonitis † 1	5/223 (2.24%)	5	3/223 (1.35%)	3	0/1 (0.00%)	0
Pneumothorax † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Pulmonary embolism † 1	5/223 (2.24%)	5	1/223 (0.45%)	1	0/1 (0.00%)	0
Respiratory failure † 1	1/223 (0.45%)	1	2/223 (0.90%)	2	0/1 (0.00%)	0
Skin and subcutaneous tissue disorders
Decubitus ulcer † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Subacute cutaneous lupus erythematosus † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Vascular disorders
Aortic aneurysm † 1	2/223 (0.90%)	2	0/223 (0.00%)	0	0/1 (0.00%)	0
Deep vein thrombosis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Embolism † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Hypertensive crisis † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Hypotension † 1	2/223 (0.90%)	2	1/223 (0.45%)	1	0/1 (0.00%)	0
Peripheral artery occlusion † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
Peripheral embolism † 1	1/223 (0.45%)	1	0/223 (0.00%)	0	0/1 (0.00%)	0
Superior vena cava syndrome † 1	2/223 (0.90%)	2	1/223 (0.45%)	1	0/1 (0.00%)	0
Vena cava thrombosis † 1	0/223 (0.00%)	0	1/223 (0.45%)	1	0/1 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab+EP		Placebo+EP		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	221/223 (99.10%)		216/223 (96.86%)		1/1 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	101/223 (45.29%)	122	96/223 (43.05%)	115	0/1 (0.00%)	0
Leukopenia † 1	49/223 (21.97%)	84	45/223 (20.18%)	70	0/1 (0.00%)	0
Neutropenia † 1	120/223 (53.81%)	217	114/223 (51.12%)	207	0/1 (0.00%)	0
Thrombocytopenia † 1	57/223 (25.56%)	85	46/223 (20.63%)	80	0/1 (0.00%)	0
Endocrine disorders
Hyperthyroidism † 1	12/223 (5.38%)	12	6/223 (2.69%)	7	0/1 (0.00%)	0
Hypothyroidism † 1	26/223 (11.66%)	27	5/223 (2.24%)	5	0/1 (0.00%)	0
Inappropriate antidiuretic hormone secretion † 1	1/223 (0.45%)	1	1/223 (0.45%)	1	1/1 (100.00%)	1
Gastrointestinal disorders
Abdominal pain † 1	15/223 (6.73%)	18	13/223 (5.83%)	13	0/1 (0.00%)	0
Abdominal pain upper † 1	13/223 (5.83%)	14	5/223 (2.24%)	5	0/1 (0.00%)	0
Constipation † 1	65/223 (29.15%)	78	59/223 (26.46%)	69	0/1 (0.00%)	0
Diarrhoea † 1	46/223 (20.63%)	67	41/223 (18.39%)	48	0/1 (0.00%)	0
Dyspepsia † 1	12/223 (5.38%)	13	7/223 (3.14%)	7	0/1 (0.00%)	0
Dysphagia † 1	12/223 (5.38%)	12	6/223 (2.69%)	6	0/1 (0.00%)	0
Nausea † 1	85/223 (38.12%)	135	96/223 (43.05%)	144	0/1 (0.00%)	0
Stomatitis † 1	14/223 (6.28%)	17	15/223 (6.73%)	17	0/1 (0.00%)	0
Vomiting † 1	36/223 (16.14%)	48	39/223 (17.49%)	49	0/1 (0.00%)	0
General disorders
Asthenia † 1	38/223 (17.04%)	46	43/223 (19.28%)	48	0/1 (0.00%)	0
Chest pain † 1	11/223 (4.93%)	11	21/223 (9.42%)	24	0/1 (0.00%)	0
Fatigue † 1	61/223 (27.35%)	76	60/223 (26.91%)	78	0/1 (0.00%)	0
Oedema peripheral † 1	17/223 (7.62%)	20	26/223 (11.66%)	32	0/1 (0.00%)	0
Pyrexia † 1	32/223 (14.35%)	37	14/223 (6.28%)	17	0/1 (0.00%)	0
Infections and infestations
Nasopharyngitis † 1	12/223 (5.38%)	15	9/223 (4.04%)	9	0/1 (0.00%)	0
Pneumonia † 1	12/223 (5.38%)	13	13/223 (5.83%)	14	0/1 (0.00%)	0
Upper respiratory tract infection † 1	17/223 (7.62%)	22	13/223 (5.83%)	16	0/1 (0.00%)	0
Urinary tract infection † 1	10/223 (4.48%)	12	8/223 (3.59%)	9	1/1 (100.00%)	1
Investigations
Alanine aminotransferase increased † 1	17/223 (7.62%)	20	21/223 (9.42%)	24	0/1 (0.00%)	0
Aspartate aminotransferase increased † 1	19/223 (8.52%)	22	13/223 (5.83%)	15	0/1 (0.00%)	0
Blood alkaline phosphatase increased † 1	12/223 (5.38%)	15	6/223 (2.69%)	8	0/1 (0.00%)	0
Blood creatinine increased † 1	15/223 (6.73%)	23	8/223 (3.59%)	8	0/1 (0.00%)	0
Weight decreased † 1	22/223 (9.87%)	24	20/223 (8.97%)	23	0/1 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	69/223 (30.94%)	85	54/223 (24.22%)	68	0/1 (0.00%)	0
Hypokalaemia † 1	15/223 (6.73%)	20	13/223 (5.83%)	19	0/1 (0.00%)	0
Hyponatraemia † 1	21/223 (9.42%)	26	16/223 (7.17%)	23	0/1 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	29/223 (13.00%)	37	19/223 (8.52%)	22	0/1 (0.00%)	0
Back pain † 1	25/223 (11.21%)	27	26/223 (11.66%)	27	0/1 (0.00%)	0
Musculoskeletal chest pain † 1	12/223 (5.38%)	14	6/223 (2.69%)	6	0/1 (0.00%)	0
Pain in extremity † 1	12/223 (5.38%)	15	13/223 (5.83%)	16	0/1 (0.00%)	0
Nervous system disorders
Dizziness † 1	31/223 (13.90%)	36	15/223 (6.73%)	17	0/1 (0.00%)	0
Dysgeusia † 1	14/223 (6.28%)	14	12/223 (5.38%)	13	0/1 (0.00%)	0
Headache † 1	29/223 (13.00%)	34	34/223 (15.25%)	41	0/1 (0.00%)	0
Psychiatric disorders
Insomnia † 1	25/223 (11.21%)	26	28/223 (12.56%)	34	0/1 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	45/223 (20.18%)	62	45/223 (20.18%)	51	0/1 (0.00%)	0
Dyspnoea † 1	37/223 (16.59%)	41	37/223 (16.59%)	41	0/1 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	75/223 (33.63%)	77	84/223 (37.67%)	87	0/1 (0.00%)	0
Dry skin † 1	13/223 (5.83%)	13	10/223 (4.48%)	10	0/1 (0.00%)	0
Erythema † 1	13/223 (5.83%)	14	4/223 (1.79%)	4	0/1 (0.00%)	0
Pruritus † 1	25/223 (11.21%)	33	18/223 (8.07%)	23	0/1 (0.00%)	0
Rash † 1	30/223 (13.45%)	39	13/223 (5.83%)	17	0/1 (0.00%)	0
Vascular disorders
Hypertension † 1	12/223 (5.38%)	15	10/223 (4.48%)	14	0/1 (0.00%)	0
Hypotension † 1	9/223 (4.04%)	11	16/223 (7.17%)	21	0/1 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1; † 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

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

Publications of Results:

Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csoszi T, Cheema PK, Rodriguez-Abreu D, Wollner M, Yang JC, Mazieres J, Orlandi FJ, Luft A, Gumus M, Kato T, Kalemkerian GP, Luo Y, Ebiana V, Pietanza MC, Kim HR; KEYNOTE-604 Investigators. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 Jul 20;38(21):2369-2379. doi: 10.1200/JCO.20.00793. Epub 2020 May 29.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03066778
• Other Study ID Numbers: 3475-604; 173744 ( Registry Identifier: JAPIC-CTI ); MK-3475-604 ( Other Identifier: Merck ); KEYNOTE-604 ( Other Identifier: Merck ); 2016-004309-15 ( EudraCT Number )
• First Submitted: February 23, 2017
• First Posted: February 28, 2017
• Results First Submitted: November 25, 2020
• Results First Posted: December 22, 2020
• Last Update Posted: October 3, 2022