Study of Pembrolizumab (MK-3475) vs Placebo for Participants With Non-small Cell Lung Cancer After Resection With or Without Standard Adjuvant Therapy (MK-3475-091/KEYNOTE-091) (PEARLS)

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ClinicalTrials.gov Identifier: NCT02504372

Recruitment Status : Active, not recruiting

First Posted : July 21, 2015

Results First Posted : February 15, 2024

Last Update Posted : February 15, 2024

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Sponsor:

Collaborators:

ETOP

European Organisation for Research and Treatment of Cancer - EORTC

Information provided by (Responsible Party):

Merck Sharp & Dohme LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Non-small Cell Lung Cancer
Interventions	Biological: Pembrolizumab Other: Placebo
Enrollment	1177

Participant Flow

Recruitment Details
Pre-assignment Details	One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Period Title: Overall Study
Started	590	587
Treated	580	581
Completed	0	0
Not Completed	590	587
Reason Not Completed
Death	136	154
Lost to Follow-up	0	2
Withdrawal of consent	25	16
Participants ongoing	429	415

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Placebo	Total
Arm/Group Description		Participants received pembrolizumab...	Participants received placebo, IV, ...	Total of all reporting groups
Arm/Group Description		Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.	Total of all reporting groups
Overall Number of Baseline Participants		590	587	1177
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	590 participants	587 participants	1177 participants
		64.1 (8.5)	64.5 (8.4)	64.3 (8.4)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Female	189 32.0%	184 31.3%	373 31.7%
	Male	401 68.0%	403 68.7%	804 68.3%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	American Indian or Alaska Native	1 0.2%	0 0.0%	1 0.1%
	Asian	107 18.1%	107 18.2%	214 18.2%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	3 0.5%	3 0.3%
	White	450 76.3%	455 77.5%	905 76.9%
	More than one race	10 1.7%	3 0.5%	13 1.1%
	Unknown or Not Reported	22 3.7%	19 3.2%	41 3.5%
Race and Ethnicity Not Collected ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Disease Stage at Baseline ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Stage IB	85 14.4%	87 14.8%	172 14.6%
	Stage II	330 55.9%	338 57.6%	668 56.8%
	Stage IIIA	175 29.7%	160 27.3%	335 28.5%
	Stage IV	0 0.0%	2 0.3%	2 0.2%
		[1] Measure Description: Participants were classified per American Joint Committee on Cancer Manual Edition 7th (AJCC V7) based on TNM classification where T refers to size and extent of primary tumor and if it invaded nearby tissue, N refers to location of nearby lymph nodes that have cancer and M refers to distant metastasis (spread of cancer to other parts). In stages I, II and III the cancer is present. The higher the number, the larger the cancer tumor and the more it has spread into nearby tissues. In stage IV, the cancer has spread to distant parts of the body. Higher numbers mean the cancer is more advanced.
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status at Baseline ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	TPS <1%	233 39.5%	232 39.5%	465 39.5%
	TPS 1-49%	189 32.0%	190 32.4%	379 32.2%
	TPS ≥50%	168 28.5%	165 28.1%	333 28.3%
		[1] Measure Description: Participants were assessed for their PD-L1 tumor expression status by immunohistochemistry assay using tumor tissue from a biopsy. Participants with a tumor proportion score (TPS) were classified as follows: <1% = PD-L1 negative, 1-49% = PD-L1 weakly positive; and ≥50% = PD-L1 strongly positive.
Adjuvant Chemotherapy at Baseline ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Yes	506 85.8%	504 85.9%	1010 85.8%
	No	84 14.2%	83 14.1%	167 14.2%
		[1] Measure Description: Participants were classified per receiving of standard adjuvant chemotherapy at baseline: Yes or No.
Geographic region ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Western Europe	303 51.4%	301 51.3%	604 51.3%
	Eastern Europe	116 19.7%	113 19.3%	229 19.5%
	Rest of the World	65 11.0%	68 11.6%	133 11.3%
	Asia	106 18.0%	105 17.9%	211 17.9%
		[1] Measure Description: Participants were classified based on their geographic region as those from: Western Europe, Easter Europe, Asia and Rest of the world.
Tumor Histology ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Squamous	192 32.5%	224 38.2%	416 35.3%
	Non-squamous	398 67.5%	363 61.8%	761 64.7%
		[1] Measure Description: Participants were classified according to tumor histology: Squamous or Non-squamous. The tumor histology determined potential treatment regimen.
Smoking status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	590 participants	587 participants	1177 participants
	Never smoker	87 14.7%	66 11.2%	153 13.0%
	Former smoker	428 72.5%	431 73.4%	859 73.0%
	Current smoker	75 12.7%	90 15.3%	165 14.0%
		[1] Measure Description: Participants were classified per centers of disease control and prevention (CDC) as: Never smoker (smoked fewer than 100 cigarettes in his/her lifetime), former smoker (smoked at least 100 cigarettes in his or her lifetime but who had quit smoking at the time of interview. and current smoker (smoked 100 cigarettes in his or her lifetime and who currently smokes cigarettes) at baseline.

Outcome Measures

1.Primary Outcome


Title	Disease-Free Survival (DFS)
Description	DFS was defined as the time from randomization to either the date of d...
Description	DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time Frame	Up to approximately 84 months

Outcome Measure Data

Analysis Population Description

All randomized participants. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	590	587
Median (95% Confidence Interval) Unit of Measure: Months
	53.8 (46.2 to 67.0)	43.0 (35.0 to 51.6)

Statistical Analysis 1

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

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.68 to 0.96
	Estimation Comments	HR and 95% confidence interval (95%CI) were based on multivariate Cox regression model with treatment adjusted by stage, PD-L1 status, adjuvant chemotherapy, region, histology, and smoking status.

2.Primary Outcome


Title	DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50%
Description	DFS in PDL-1 strong positive participants with TPS ≥50% was defi...
Description	DFS in PDL-1 strong positive participants with TPS ≥50% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time Frame	Up to approximately 84 months

Outcome Measure Data

Analysis Population Description

All randomized PDL-1 strong positive participants with TPS ≥50%. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	168	165
Median (95% Confidence Interval) Unit of Measure: Months
	67.0 ^[1] (47.8 to NA)	47.6 ^[1] (36.4 to NA)

[1]

NA = Upper limit DFS was not reached at the time of last disease assessment due to insufficient number of participants with events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.13499
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	One-sided p-value was based on the permutation test with multivariate Cox regression model.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.59 to 1.16
	Estimation Comments	HR and 95% confidence interval (95%CI) were based on multivariate Cox regression model with treatment adjusted by stage, PD-L1 status, adjuvant chemotherapy, region, histology, and smoking status.

3.Secondary Outcome


Title	DFS in PDL-1 Strong Positive Participants With TPS ≥1%
Description	DFS in PDL-1 strong positive participants with TPS ≥1% was defin...
Description	DFS in PDL-1 strong positive participants with TPS ≥1% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time Frame	Up to approximately 84 months

Outcome Measure Data

Analysis Population Description

All randomized PDL-1 strong positive participants with TPS ≥1%. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	357	355
Median (95% Confidence Interval) Unit of Measure: Months
	58.7 (46.2 to 76.7)	42.8 (35.0 to 57.8)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.01327
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	One-sided p-value was based on the permutation test with multivariate Cox regression model.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.62 to 0.97
	Estimation Comments	HR and 95% confidence interval (95%CI) were based on multivariate Cox regression model with treatment adjusted by stage, PD-L1 status, adjuvant chemotherapy, region, histology, and smoking status.

4.Secondary Outcome


Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to the date of death.
Description	OS was defined as the time from randomization to the date of death.
Time Frame	Up to approximately 132 months

Outcome Measure Data Not Reported

5.Secondary Outcome


Title	OS in PDL-1 Strong Positive Participants With TPS ≥50%
Description	OS in PDL-1 Strong Positive Participants with TPS ≥50% was defin...
Description	OS in PDL-1 Strong Positive Participants with TPS ≥50% was defined as the time from randomization to the date of death.
Time Frame	Up to approximately 132 months

Outcome Measure Data Not Reported

6.Secondary Outcome


Title	OS in PDL-1 Strong Positive Participants With TPS ≥1%
Description	OS in PDL-1 Strong Positive Participants with TPS ≥1% was define...
Description	OS in PDL-1 Strong Positive Participants with TPS ≥1% was defined as the time from randomization to the date of death.
Time Frame	Up to approximately 132 months

Outcome Measure Data Not Reported

7.Secondary Outcome


Title	Lung Cancer Specific Survival (LCSS)
Description	LCSS was defined as the time from randomization to the date of death (...
Description	LCSS was defined as the time from randomization to the date of death (due to lung cancer specifically).
Time Frame	Up to approximately 132 months

Outcome Measure Data Not Reported

8.Secondary Outcome


Title	Number of Participants Who Experienced 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 or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can 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. The number of participants who experienced an AE were reported.
Time Frame	Up to approximately 22 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	580	581
Measure Type: Count of Participants Unit of Measure: Participants
	556 95.9%	529 91.0%

9.Secondary Outcome


Title	Number of Participants Who Discontinued Study Treatment Due to an 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 or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can 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. The number of participants who discontinued study treatment due to an AE were reported.
Time Frame	Up to approximately 19 months

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	580	581
Measure Type: Count of Participants Unit of Measure: Participants
	116 20.0%	34 5.9%

10.Other Pre-specified Outcome


Title	DFS at 68 Months
Description	DFS was defined as the time from randomization to either the date of d...
Description	DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time Frame	Up to approximately 68 months

Outcome Measure Data

Analysis Population Description

All randomized participants. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	Participants received pembrolizumab...	Participants received placebo, IV, ...
Arm/Group Description:	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.	Participants received placebo, IV, every 3 weeks, for one year.
Overall Number of Participants Analyzed	590	587
Median (95% Confidence Interval) Unit of Measure: Months
	53.6 ^[1] (39.2 to NA)	42.0 ^[1] (31.3 to NA)

[1]

NA = Upper limit DFS was not reached at the time of last disease assessment due to insufficient number of participants with events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.00143
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	One-sided p-value was based on the permutation test with multivariate Cox regression model.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95% 0.63 to 0.91
	Estimation Comments	HR and 95% confidence interval (95%CI) were based on multivariate Cox regression model with treatment adjusted by stage, PD-L1 status, adjuvant chemotherapy, region, histology, and smoking status.

Adverse Events

Time Frame	Up to approximately 86 months
Adverse Event Reporting Description	All-cause mortality was reported on all randomized participants. Serious and non-serious adverse events were reported on all randomized participants who received at least one dose of study treatment. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.

Arm/Group Title	Pembrolizumab		Placebo
Arm/Group Description	Participants received pembrolizumab...		Participants received placebo, IV, ...
Arm/Group Description	Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year.		Participants received placebo, IV, every 3 weeks, for one year.
All-Cause Mortality
	Pembrolizumab		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	136/590 (23.05%)		154/587 (26.24%)
Serious Adverse Events Serious Adverse Events
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	142/580 (24.48%)		90/581 (15.49%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Cardiac disorders
Angina pectoris ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Atrial fibrillation ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Atrial tachycardia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Cardiac arrest ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Cardiac failure congestive ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Cardiogenic shock ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Coronary artery disease ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Myocardial infarction ^† 1	2/580 (0.34%)	3	3/581 (0.52%)	3
Myocardial ischaemia ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Myocarditis ^† 1	5/580 (0.86%)	7	0/581 (0.00%)	0
Pericardial effusion ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Supraventricular tachycardia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Tachyarrhythmia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Endocrine disorders
Adrenal insufficiency ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Glucocorticoid deficiency ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hyperthyroidism ^† 1	2/580 (0.34%)	3	0/581 (0.00%)	0
Hypophysitis ^† 1	4/580 (0.69%)	4	0/581 (0.00%)	0
Hypothyroidism ^† 1	2/580 (0.34%)	3	0/581 (0.00%)	0
Eye disorders
Cataract ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Colitis ^† 1	4/580 (0.69%)	5	2/581 (0.34%)	4
Diarrhoea ^† 1	7/580 (1.21%)	11	1/581 (0.17%)	1
Diverticular perforation ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Erosive oesophagitis ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Gastric ulcer haemorrhage ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Ileus paralytic ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Immune-mediated enterocolitis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Impaired gastric emptying ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Melaena ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Nausea ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Oesophagitis ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Pancreatitis ^† 1	0/580 (0.00%)	0	2/581 (0.34%)	4
Vomiting ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
General disorders
Asthenia ^† 1	2/580 (0.34%)	2	1/581 (0.17%)	1
Cardiac death ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Death ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Fatigue ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
General physical health deterioration ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Performance status decreased ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Pyrexia ^† 1	1/580 (0.17%)	2	3/581 (0.52%)	3
Sudden death ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Cholecystitis ^† 1	3/580 (0.52%)	3	1/581 (0.17%)	1
Cholecystitis acute ^† 1	2/580 (0.34%)	3	0/581 (0.00%)	0
Drug-induced liver injury ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Hepatic failure ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hepatic function abnormal ^† 1	1/580 (0.17%)	4	0/581 (0.00%)	0
Hepatitis ^† 1	3/580 (0.52%)	3	0/581 (0.00%)	0
Hepatotoxicity ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Immune-mediated hepatitis ^† 1	3/580 (0.52%)	3	0/581 (0.00%)	0
Jaundice ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Immune system disorders
Anaphylactic shock ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hypersensitivity ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Sarcoidosis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Infections and infestations
Appendicitis ^† 1	2/580 (0.34%)	2	1/581 (0.17%)	1
Atypical pneumonia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Bronchitis ^† 1	3/580 (0.52%)	4	1/581 (0.17%)	1
COVID-19 ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
COVID-19 pneumonia ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Clostridium difficile infection ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Cytomegalovirus infection ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Diverticulitis ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Erysipelas ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Gastroenteritis ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Large intestine infection ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Lower respiratory tract infection ^† 1	3/580 (0.52%)	3	2/581 (0.34%)	2
Lower respiratory tract infection bacterial ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Penile infection ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Pneumocystis jirovecii pneumonia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Pneumonia ^† 1	13/580 (2.24%)	15	9/581 (1.55%)	11
Pneumonia bacterial ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	2
Post procedural pneumonia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Pyelonephritis ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Respiratory tract infection ^† 1	1/580 (0.17%)	3	0/581 (0.00%)	0
Sepsis ^† 1	3/580 (0.52%)	4	3/581 (0.52%)	3
Septic shock ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Skin infection ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Staphylococcal sepsis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Upper respiratory tract infection ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Urinary tract infection ^† 1	3/580 (0.52%)	3	2/581 (0.34%)	2
Urosepsis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Vascular device infection ^† 1	0/580 (0.00%)	0	2/581 (0.34%)	2
Viral infection ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Injury, poisoning and procedural complications
Alcohol poisoning ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Ankle fracture ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Contusion ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Facial bones fracture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Fall ^† 1	3/580 (0.52%)	3	0/581 (0.00%)	0
Femoral neck fracture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Femur fracture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Hand fracture ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hip fracture ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Incision site discharge ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Joint dislocation ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Lower limb fracture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Meniscus injury ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Poisoning ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Procedural pneumothorax ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Spinal fracture ^† 1	0/580 (0.00%)	0	2/581 (0.34%)	2
Sternal fracture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Tendon rupture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Wound ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Wound dehiscence ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Wrist fracture ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Investigations
Blood creatinine increased ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Troponin T increased ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Hypercalcaemia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	3
Hyperkalaemia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Hyponatraemia ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	2
Type 1 diabetes mellitus ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Arthritis ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Back disorder ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Pathological fracture ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Polymyalgia rheumatica ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Sarcopenia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Spinal osteoarthritis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Adenocarcinoma pancreas ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Bladder transitional cell carcinoma ^† 1	2/580 (0.34%)	2	1/581 (0.17%)	1
Clear cell renal cell carcinoma ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Colon cancer ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Gastric cancer ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Gastrointestinal stromal tumour ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Haemangioma ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Lung adenocarcinoma ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Lymphoma ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Metastases to central nervous system ^† 1	0/580 (0.00%)	0	2/581 (0.34%)	2
Neuroendocrine tumour ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Oesophageal adenocarcinoma ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Oesophageal carcinoma ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Pancreatic carcinoma ^† 1	0/580 (0.00%)	0	2/581 (0.34%)	2
Prostate cancer ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Prostate cancer recurrent ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Rectal cancer ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	3
Small cell lung cancer ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Small intestine carcinoma ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Squamous cell carcinoma of the tongue ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Superficial spreading melanoma stage unspecified ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Tonsil cancer ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Tracheal cancer ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Ureteric cancer ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Nervous system disorders
Ataxia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Brain stem stroke ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Cerebral infarction ^† 1	1/580 (0.17%)	1	1/581 (0.17%)	1
Cerebral ischaemia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Cerebrovascular accident ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Dizziness ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Dysaesthesia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Dysarthria ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Intensive care unit acquired weakness ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Ischaemic stroke ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Retrograde amnesia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Superior sagittal sinus thrombosis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Syncope ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Transient ischaemic attack ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Product Issues
Device dislocation ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Psychiatric disorders
Completed suicide ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Confusional state ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	3
Neurosis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	2/580 (0.34%)	2	0/581 (0.00%)	0
Azotaemia ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Nephrolithiasis ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Renal failure ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Urinary retention ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial haemorrhage ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Bronchiectasis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	5/580 (0.86%)	8	1/581 (0.17%)	2
Cough ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Dyspnoea ^† 1	4/580 (0.69%)	4	4/581 (0.69%)	4
Immune-mediated lung disease ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Interstitial lung disease ^† 1	3/580 (0.52%)	5	0/581 (0.00%)	0
Lung disorder ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Pleuritic pain ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Pneumonitis ^† 1	12/580 (2.07%)	15	4/581 (0.69%)	4
Pneumothorax ^† 1	2/580 (0.34%)	2	1/581 (0.17%)	1
Pulmonary embolism ^† 1	3/580 (0.52%)	3	0/581 (0.00%)	0
Pulmonary fibrosis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Respiratory failure ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Skin and subcutaneous tissue disorders
Diabetic foot ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Pruritus ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Rash erythematous ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Rash macular ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Rash maculo-papular ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Scar pain ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Stevens-Johnson syndrome ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Urticaria ^† 1	1/580 (0.17%)	2	0/581 (0.00%)	0
Vascular disorders
Aortic aneurysm ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Aortic aneurysm rupture ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	2
Arterial thrombosis ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
Giant cell arteritis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Hypertensive crisis ^† 1	1/580 (0.17%)	1	0/581 (0.00%)	0
Peripheral ischaemia ^† 1	0/580 (0.00%)	0	1/581 (0.17%)	1
1 Term from vocabulary, MedDRA 25.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	510/580 (87.93%)		458/581 (78.83%)
Endocrine disorders
Hyperthyroidism ^† 1	62/580 (10.69%)	65	17/581 (2.93%)	18
Hypothyroidism ^† 1	120/580 (20.69%)	148	27/581 (4.65%)	29
Gastrointestinal disorders
Constipation ^† 1	35/580 (6.03%)	38	41/581 (7.06%)	53
Diarrhoea ^† 1	104/580 (17.93%)	179	82/581 (14.11%)	160
Nausea ^† 1	52/580 (8.97%)	64	37/581 (6.37%)	48
General disorders
Asthenia ^† 1	44/580 (7.59%)	66	32/581 (5.51%)	39
Fatigue ^† 1	96/580 (16.55%)	131	89/581 (15.32%)	118
Influenza like illness ^† 1	34/580 (5.86%)	39	32/581 (5.51%)	36
Pyrexia ^† 1	31/580 (5.34%)	34	32/581 (5.51%)	48
Infections and infestations
Nasopharyngitis ^† 1	50/580 (8.62%)	65	32/581 (5.51%)	44
Upper respiratory tract infection ^† 1	52/580 (8.97%)	63	55/581 (9.47%)	68
Investigations
Alanine aminotransferase increased ^† 1	46/580 (7.93%)	75	34/581 (5.85%)	42
Aspartate aminotransferase increased ^† 1	41/580 (7.07%)	61	31/581 (5.34%)	40
Blood creatinine increased ^† 1	38/580 (6.55%)	60	32/581 (5.51%)	52
Weight decreased ^† 1	39/580 (6.72%)	59	25/581 (4.30%)	36
Weight increased ^† 1	132/580 (22.76%)	260	168/581 (28.92%)	314
Metabolism and nutrition disorders
Decreased appetite ^† 1	41/580 (7.07%)	49	26/581 (4.48%)	28
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	107/580 (18.45%)	152	72/581 (12.39%)	99
Back pain ^† 1	45/580 (7.76%)	51	46/581 (7.92%)	57
Myalgia ^† 1	37/580 (6.38%)	47	15/581 (2.58%)	16
Pain in extremity ^† 1	18/580 (3.10%)	20	31/581 (5.34%)	38
Nervous system disorders
Headache ^† 1	45/580 (7.76%)	67	46/581 (7.92%)	60
Paraesthesia ^† 1	18/580 (3.10%)	19	32/581 (5.51%)	39
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	87/580 (15.00%)	101	98/581 (16.87%)	130
Dyspnoea ^† 1	66/580 (11.38%)	87	72/581 (12.39%)	91
Pneumonitis ^† 1	32/580 (5.52%)	52	15/581 (2.58%)	20
Productive cough ^† 1	37/580 (6.38%)	46	15/581 (2.58%)	18
Skin and subcutaneous tissue disorders
Dry skin ^† 1	31/580 (5.34%)	34	21/581 (3.61%)	25
Pruritus ^† 1	125/580 (21.55%)	167	74/581 (12.74%)	115
Rash ^† 1	49/580 (8.45%)	69	29/581 (4.99%)	37
Rash maculo-papular ^† 1	43/580 (7.41%)	62	20/581 (3.44%)	27
Vascular disorders
Hypertension ^† 1	67/580 (11.55%)	160	74/581 (12.74%)	184
1 Term from vocabulary, MedDRA 25.1 † 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 30 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

Results Point of Contact

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

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

O'Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 - PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1274-1286. doi: 10.1016/S1470-2045(22)00518-6. Epub 2022 Sep 12.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT02504372
Other Study ID Numbers:	3475-091 EORTC-1416-LCG ( Other Identifier: EORTC ) 163457 ( Registry Identifier: JAPIC-CTI ) MK-3475-091 ( Other Identifier: Merck ) KEYNOTE-091 ( Other Identifier: Merck ) 2015-000575-27 ( EudraCT Number )
First Submitted:	July 20, 2015
First Posted:	July 21, 2015
Results First Submitted:	January 9, 2024
Results First Posted:	February 15, 2024
Last Update Posted:	February 15, 2024

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