Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)

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ClinicalTrials.gov Identifier: NCT02362594

Recruitment Status : Active, not recruiting

First Posted : February 13, 2015

Results First Posted : January 4, 2019

Last Update Posted : August 21, 2023

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Sponsor:

Collaborator:

European Organisation for Research and Treatment of Cancer

Information provided by (Responsible Party):

Merck Sharp & Dohme LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Melanoma
Interventions	Biological: pembrolizumab Drug: placebo
Enrollment	1019

Participant Flow

Recruitment Details
Pre-assignment Details	As of the 02-Oct-2017 interim database cut-off date, of the 1019 randomized participants in Part 1, 544 had completed Part 1 and 62 were continuing in Part 1. This interim results disclosure is for Part 1 only.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description	In Part 1, participants received pembrolizumab 200 mg intravenously (IV) as post-surgery therapy every 3 weeks (Q3W) for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Period Title: Overall Study
Started	514	505
Treated	509	502
Continuing Part 1 Adjuvant Therapy	41	21
Completed ^[1]	264	280
Not Completed	250	225
[1] Completed Part 1 Adjuvant Therapy

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Placebo	Total
Arm/Group Description		In Part 1, participants received pe...	In Part 1, participants received pl...	Total of all reporting groups
Arm/Group Description		In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.	Total of all reporting groups
Overall Number of Baseline Participants		514	505	1019
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	514 participants	505 participants	1019 participants
		53.9 (13.6)	53.7 (14.2)	53.8 (13.9)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	514 participants	505 participants	1019 participants
	Female	190 37.0%	201 39.8%	391 38.4%
	Male	324 63.0%	304 60.2%	628 61.6%
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.
Programmed Death-Ligand 1 (PD-L1) Tumor Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
PD-L1 Positive	Number Analyzed	514 participants	505 participants	1019 participants
PD-L1 Positive		428 83.3%	425 84.2%	853 83.7%
PD-L1 Negative	Number Analyzed	514 participants	505 participants	1019 participants
PD-L1 Negative		59 11.5%	57 11.3%	116 11.4%
Undetermined	Number Analyzed	514 participants	505 participants	1019 participants
Undetermined		27 5.3%	23 4.6%	50 4.9%
		[1] Measure Description: Tumor PD-L1 status was assessed by immunohistochemistry (IHC) and recorded as positive (≥1% PD-L1 IHC), negative (<1% PD-L1 IHC), or undetermined level of expression (indeterminate PD-L1 IHC).
Melanoma Stage ^[1] Measure Type: Count of Participants Unit of measure: Participants
Stage IIIA (> 1 mm)	Number Analyzed	514 participants	505 participants	1019 participants
Stage IIIA (> 1 mm)		80 15.6%	80 15.8%	160 15.7%
Stage IIIB	Number Analyzed	514 participants	505 participants	1019 participants
Stage IIIB		237 46.1%	230 45.5%	467 45.8%
Stage IIIC (1-3 LN+)	Number Analyzed	514 participants	505 participants	1019 participants
Stage IIIC (1-3 LN+)		95 18.5%	93 18.4%	188 18.4%
Stage IIIC (≥4 LN+)	Number Analyzed	514 participants	505 participants	1019 participants
Stage IIIC (≥4 LN+)		102 19.8%	102 20.2%	204 20.0%
		[1] Measure Description: Participants were stratified by melanoma stage using the American Joint Committee on Cancer (AJCC) 7th edition stage as follows: Stage IIIA (with >1 mm metastasis), Stage IIIB, Stage IIIC with 1-3 positive lymph nodes (LN+), and Stage IIIC with ≥4 LN+.
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	514 participants	505 participants	1019 participants
	North America	38 7.4%	37 7.3%	75 7.4%
	Europe	341 66.3%	336 66.5%	677 66.4%
	Australia/New Zealand	111 21.6%	112 22.2%	223 21.9%
	Other	24 4.7%	20 4.0%	44 4.3%

Outcome Measures

1.Primary Outcome


Title	Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants
Description	RFS was defined as the time between the date of randomization and the ...
Description	RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants in both treatment arms of Part 1.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized participants in Part 1.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	514	505
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	82.2 (78.6 to 85.3)	73.3 (69.2 to 77.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Placebo
	Comments	Comparison of RFS time-to-event distribution between the 2 treatment arms was based on Cox regression model with treatment as a covariate stratified by stage (IIIA [>1 mm metastasis] vs. IIIB vs. IIIC 1-3 nodes vs. IIIC ≥4 nodes) as indicated at randomization.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value based on log-rank test.
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 98.4% 0.43 to 0.74
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression
Description	RFS was defined as the time between the date of randomization and the ...
Description	RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants with PD-L1-positive tumors in both treatment arms of Part 1.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized participants in Part 1 with PD-L1-positive tumors.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	428	425
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	83.8 (80.0 to 87.0)	75.4 (71.0 to 79.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Placebo
	Comments	Comparison of RFS time-to-event distribution between the 2 treatment arms (PD-L1-positive participants) was based on Cox regression model with treatment as a covariate stratified by stage (IIIA [>1 mm metastasis] vs. IIIB vs. IIIC 1-3 nodes vs. IIIC ≥4 nodes) as indicated at randomization.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value based on log-rank test.
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95.0% 0.42 to 0.69
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Distant Metastases-free Survival (DMFS) in All Participants
Description	DMFS will be defined as the time between the date of randomization and...
Description	DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants in both treatment arms.
Time Frame	Up to 10 years

Outcome Measure Data Not Reported

4.Secondary Outcome


Title	Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression
Description	Description: ...
Description	Description: DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
Time Frame	Up to 10 years

Outcome Measure Data Not Reported

5.Secondary Outcome


Title	Overall Survival (OS) for All Participants
Description	OS will be defined as the time from the date of randomization to the d...
Description	OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants in both treatment arms.
Time Frame	Up to 10 years

Outcome Measure Data Not Reported

6.Secondary Outcome


Title	Overall Survival (OS) for Participants With PD-L1-positive Tumor Expression
Description	OS will be defined as the time from the date of randomization to the d...
Description	OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
Time Frame	Up to 10 years

Outcome Measure Data Not Reported

7.Secondary Outcome


Title	Number of Participants Who Experienced At Least 1 Adverse Event (AE)
Description	An AE is defined as "any untoward medical occurrence in a partici...
Description	An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who experienced at least 1 AE was reported for all participants in each treatment arm.
Time Frame	Up to 22 months

Outcome Measure Data

Analysis Population Description

All randomized participants in Part 1 who received at least 1 dose of study treatment.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	509	502
Measure Type: Count of Participants Unit of Measure: Participants
	475 93.3%	453 90.2%

8.Secondary Outcome


Title	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Description	An AE is defined as "any untoward medical occurrence in a partici...
Description	An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who discontinued study treatment due to an AE was reported for all participants in each treatment arm.
Time Frame	Up to 22 months

Outcome Measure Data

Analysis Population Description

All randomized participants in Part 1 who received at least 1 dose of study treatment.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	509	502
Measure Type: Count of Participants Unit of Measure: Participants
	70 13.8%	18 3.6%

9.Secondary Outcome


Title	Clearance (CL) of Pembrolizumab
Description	Blood samples were to be collected at pre-specified time points and pl...
Description	Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab CL, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following IV pembrolizumab administration. Samples were not collected and this analysis was not performed.
Time Frame	Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.

Outcome Measure Data

Analysis Population Description

As pre-specified by the protocol, pembrolizumab CL was not analyzed as planned and no data were collected since by the time of the interim analysis, pembrolizumab pharmacokinetics (PK) in melanoma patients had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

10.Secondary Outcome


Title	Volume of Distribution (V) of Pembrolizumab
Description	Blood samples were to be collected at pre-specified time points and pl...
Description	Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab V, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. Samples were not collected and this analysis was not performed.
Time Frame	Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.

Outcome Measure Data

Analysis Population Description

As pre-specified by the protocol, pembrolizumab V was not analyzed as planned and no data were collected since by the time of the interim analysis, pembrolizumab PK in melanoma patients had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

11.Secondary Outcome


Title	Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment
Description	Pre- and post-baseline serum samples from participants treated with pe...
Description	Pre- and post-baseline serum samples from participants treated with pembrolizumab were analyzed for ADA by means of a neutralizing antibody assay which assessed the ability of ADA to block (neutralize) binding of pembrolizumab to Programmed Cell Death-1 (PD-1) protein. Overall immunogenicity was defined as the number of treatment emergent positive participants based on the total number of evaluable participants (treatment emergent positive, non-treatment emergent positive and negative immunogenicity status).
Time Frame	Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.

Outcome Measure Data

Analysis Population Description

All randomized participants in Part 1 who had at least one ADA sample available after treatment with pembrolizumab and who had treatment emergent positive, non-treatment emergent positive, or negative immunogenicity status. Participants receiving Placebo treatment in Part 1 were not analyzed for ADA.


Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description:	In Part 1, participants received pe...	In Part 1, participants received pl...
Arm/Group Description:	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.	In Part 1, participants received placebo IV as post-surgery therapy Q3W.
Overall Number of Participants Analyzed	495	0
Measure Type: Count of Participants Unit of Measure: Participants
Negative	473 95.6%
Non-Treatment emergent positive	5 1.0%
Treatment emergent positive	17 3.4%

Adverse Events

Time Frame	Up to 29 months (through database cut-off date of 02-Oct-2017)
Adverse Event Reporting Description	All-Cause Mortality was reported for all randomized participants in Part 1. Serious AEs and Other AEs were reported for all randomized participants who received at least 1 dose of study treatment in Part 1. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Arm/Group Title	Pembrolizumab		Placebo
Arm/Group Description	In Part 1, participants received pe...		In Part 1, participants received pl...
Arm/Group Description	In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year.		In Part 1, participants received placebo IV as post-surgery therapy Q3W.
All-Cause Mortality
	Pembrolizumab		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	25/514 (4.86%)		35/505 (6.93%)
Serious Adverse Events Serious Adverse Events
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	128/509 (25.15%)		82/502 (16.33%)
Cardiac disorders
Acute myocardial infarction ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Atrial fibrillation ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Autoimmune pericarditis ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Cardiac failure congestive ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Myocarditis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Ventricular tachycardia ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Endocrine disorders
Adrenocortical insufficiency acute ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Hyperthyroidism ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Hypophysitis ^† 1	3/509 (0.59%)	3	0/502 (0.00%)	0
Hypopituitarism ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Secondary adrenocortical insufficiency ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Thyroiditis ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Eye disorders
Conjunctivitis allergic ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Abdominal pain upper ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Aptyalism ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Autoimmune colitis ^† 1	3/509 (0.59%)	6	0/502 (0.00%)	0
Colitis ^† 1	8/509 (1.57%)	11	0/502 (0.00%)	0
Constipation ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Diarrhoea ^† 1	5/509 (0.98%)	9	2/502 (0.40%)	2
Enteritis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Food poisoning ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Gastritis ^† 1	2/509 (0.39%)	3	0/502 (0.00%)	0
Haemorrhoids ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	3
Ileus ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Large intestine perforation ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Nausea ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Oesophageal haemorrhage ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Oral lichen planus ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Pancreatitis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Pancreatitis acute ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Small intestinal perforation ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Vomiting ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
General disorders
Discomfort ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Fatigue ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Granuloma ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Oedema ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Papillitis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Pyrexia ^† 1	4/509 (0.79%)	8	0/502 (0.00%)	0
Systemic inflammatory response syndrome ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Cholecystitis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Cholelithiasis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Hepatitis ^† 1	2/509 (0.39%)	8	0/502 (0.00%)	0
Immune system disorders
Anaphylactic reaction ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Sarcoidosis ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Infections and infestations
Bronchitis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Cellulitis ^† 1	3/509 (0.59%)	4	7/502 (1.39%)	8
Cholecystitis infective ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Diverticulitis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Erysipelas ^† 1	2/509 (0.39%)	2	4/502 (0.80%)	4
Gastroenteritis viral ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Infected seroma ^† 1	0/509 (0.00%)	0	2/502 (0.40%)	2
Infection ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Lung infection ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Pneumonia ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Post procedural cellulitis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Respiratory tract infection viral ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Skin infection ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
Soft tissue infection ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Subcutaneous abscess ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Upper respiratory tract infection ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Viral infection ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Vulvitis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Injury, poisoning and procedural complications
Animal bite ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Post procedural haematoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Spinal column injury ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Subarachnoid haemorrhage ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Synovial rupture ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Wound necrosis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	2/509 (0.39%)	3	0/502 (0.00%)	0
Aspartate aminotransferase increased ^† 1	3/509 (0.59%)	4	0/502 (0.00%)	0
Gamma-glutamyltransferase increased ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Diabetic ketoacidosis ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Hypercreatininaemia ^† 1	1/509 (0.20%)	4	0/502 (0.00%)	0
Hyperglycaemia ^† 1	2/509 (0.39%)	5	0/502 (0.00%)	0
Hyponatraemia ^† 1	1/509 (0.20%)	2	2/502 (0.40%)	3
Type 1 diabetes mellitus ^† 1	3/509 (0.59%)	5	0/502 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Fasciitis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Intervertebral disc protrusion ^† 1	1/509 (0.20%)	3	2/502 (0.40%)	2
Myositis ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Rheumatoid arthritis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Angiolipoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Basal cell carcinoma ^† 1	17/509 (3.34%)	24	25/502 (4.98%)	36
Benign lymph node neoplasm ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Benign neoplasm of testis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Bowen's disease ^† 1	4/509 (0.79%)	4	1/502 (0.20%)	1
Choroid melanoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Hepatocellular carcinoma ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Intracranial tumour haemorrhage ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Invasive ductal breast carcinoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Keratoacanthoma ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Lentigo maligna ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Leydig cell tumour of the testis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Malignant melanoma ^† 1	3/509 (0.59%)	3	3/502 (0.60%)	4
Malignant melanoma in situ ^† 1	1/509 (0.20%)	1	6/502 (1.20%)	6
Mantle cell lymphoma ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Melanocytic naevus ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Meningioma ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Metastases to central nervous system ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
Nodular melanoma ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Prostate cancer ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
Rectal adenocarcinoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Renal cell carcinoma ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
Squamous cell carcinoma ^† 1	6/509 (1.18%)	10	3/502 (0.60%)	4
Squamous cell carcinoma of skin ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Superficial spreading melanoma stage unspecified ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	2
Thyroid cancer ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Nervous system disorders
Carotid artery aneurysm ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Cerebrovascular accident ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Dizziness ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Facial paralysis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Headache ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Myasthenia gravis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Peripheral sensory neuropathy ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Sciatica ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Transient ischaemic attack ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Psychiatric disorders
Anxiety ^† 1	1/509 (0.20%)	1	1/502 (0.20%)	1
Renal and urinary disorders
Acute kidney injury ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Autoimmune nephritis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Glomerulosclerosis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Nephritis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	4
Nephrolithiasis ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Renal colic ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Tubulointerstitial nephritis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Urinary retention ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Interstitial lung disease ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Pleural effusion ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Pneumonitis ^† 1	7/509 (1.38%)	8	0/502 (0.00%)	0
Pneumothorax ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Pulmonary embolism ^† 1	2/509 (0.39%)	2	0/502 (0.00%)	0
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Lichenoid keratosis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Psoriasis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Rash ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Rash maculo-papular ^† 1	1/509 (0.20%)	3	0/502 (0.00%)	0
Urticaria ^† 1	1/509 (0.20%)	2	0/502 (0.00%)	0
Surgical and medical procedures
Appendicectomy ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Vascular disorders
Deep vein thrombosis ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Haematoma ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
Hypotension ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Lymphoedema ^† 1	1/509 (0.20%)	1	0/502 (0.00%)	0
Venous thrombosis ^† 1	0/509 (0.00%)	0	1/502 (0.20%)	1
1 Term from vocabulary, MedDRA 20.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	443/509 (87.03%)		409/502 (81.47%)
Endocrine disorders
Hyperthyroidism ^† 1	52/509 (10.22%)	61	6/502 (1.20%)	6
Hypothyroidism ^† 1	75/509 (14.73%)	93	14/502 (2.79%)	14
Gastrointestinal disorders
Abdominal pain ^† 1	37/509 (7.27%)	40	31/502 (6.18%)	37
Constipation ^† 1	34/509 (6.68%)	37	29/502 (5.78%)	32
Diarrhoea ^† 1	140/509 (27.50%)	238	129/502 (25.70%)	234
Dry mouth ^† 1	30/509 (5.89%)	32	10/502 (1.99%)	10
Nausea ^† 1	88/509 (17.29%)	112	73/502 (14.54%)	103
Vomiting ^† 1	40/509 (7.86%)	55	22/502 (4.38%)	25
General disorders
Asthenia ^† 1	56/509 (11.00%)	93	42/502 (8.37%)	71
Fatigue ^† 1	168/509 (33.01%)	247	168/502 (33.47%)	232
Influenza like illness ^† 1	55/509 (10.81%)	73	38/502 (7.57%)	47
Infections and infestations
Nasopharyngitis ^† 1	44/509 (8.64%)	54	25/502 (4.98%)	26
Upper respiratory tract infection ^† 1	39/509 (7.66%)	49	30/502 (5.98%)	39
Investigations
Alanine aminotransferase increased ^† 1	35/509 (6.88%)	41	24/502 (4.78%)	30
Weight decreased ^† 1	55/509 (10.81%)	69	39/502 (7.77%)	64
Weight increased ^† 1	63/509 (12.38%)	96	82/502 (16.33%)	117
Metabolism and nutrition disorders
Decreased appetite ^† 1	36/509 (7.07%)	40	13/502 (2.59%)	15
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	79/509 (15.52%)	130	72/502 (14.34%)	98
Back pain ^† 1	34/509 (6.68%)	37	54/502 (10.76%)	69
Myalgia ^† 1	35/509 (6.88%)	40	25/502 (4.98%)	29
Pain in extremity ^† 1	22/509 (4.32%)	26	30/502 (5.98%)	34
Nervous system disorders
Dizziness ^† 1	26/509 (5.11%)	29	31/502 (6.18%)	38
Headache ^† 1	95/509 (18.66%)	135	93/502 (18.53%)	126
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	70/509 (13.75%)	88	55/502 (10.96%)	66
Dyspnoea ^† 1	46/509 (9.04%)	50	25/502 (4.98%)	26
Skin and subcutaneous tissue disorders
Pruritus ^† 1	99/509 (19.45%)	138	58/502 (11.55%)	74
Rash ^† 1	67/509 (13.16%)	90	43/502 (8.57%)	51
Rash maculo-papular ^† 1	27/509 (5.30%)	44	24/502 (4.78%)	26
Vascular disorders
Hypertension ^† 1	74/509 (14.54%)	178	77/502 (15.34%)	209
Lymphoedema ^† 1	26/509 (5.11%)	28	36/502 (7.17%)	37
1 Term from vocabulary, MedDRA 20.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

All draft publications, including abstracts or detailed summaries of any proposed presentations, must be submitted to the Sponsor at the earliest practicable time for review, not less than 30 days before submission or presentation unless otherwise set forth in the clinical trial agreement. Sponsor shall have the right to delete any confidential information contained in any proposed presentation or abstract and may delay publication for up to 60 days for purposes of filing a patent application.

Results Point of Contact

Layout table for Results Point of Contact information

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

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

Kennedy OJ, Kicinski M, Valpione S, Gandini S, Suciu S, Blank CU, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Robert C, Eggermont AMM, Lorigan P, Mandala M. Prognostic and predictive value of beta-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma. Eur J Cancer. 2022 Apr;165:97-112. doi: 10.1016/j.ejca.2022.01.017. Epub 2022 Feb 24.

Bottomley A, Coens C, Mierzynska J, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. doi: 10.1016/S1470-2045(21)00081-4. Epub 2021 Apr 12.

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. doi: 10.1016/S1470-2045(21)00065-6. Epub 2021 Apr 12.

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. doi: 10.1200/JCO.20.02110. Epub 2020 Sep 18.

Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, Krepler C, Ibrahim N, Marreaud S, van Akkooi A, Robert C, Suciu S. Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020 Apr 1;6(4):519-527. doi: 10.1001/jamaoncol.2019.5570.

van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

Layout table for additonal information

Responsible Party:	Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:	NCT02362594
Other Study ID Numbers:	3475-054 1325-MG ( Other Identifier: European Organisation for Research and Treatment of Cancer ) 163277 ( Registry Identifier: JAPIC-CTI ) KEYNOTE-054 ( Other Identifier: Merck ) MK-3475-054 ( Other Identifier: Merck ) 2014-004944-37 ( EudraCT Number )
First Submitted:	February 9, 2015
First Posted:	February 13, 2015
Results First Submitted:	December 10, 2018
Results First Posted:	January 4, 2019
Last Update Posted:	August 21, 2023

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