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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02362594
• Collaborator: European Organisation for Research and Treatment of Cancer (Other)
• Enrollment: 1,019
• Arms: 2
• Anticipated Duration (Months): 132.5

Study Details

Study Description

Brief Summary

This study will assess whether post-surgery therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk participants with melanoma (Stage IIIA [> 1 mm metastasis], IIIB and IIIC). The study will also assess whether pembrolizumab improves RFS versus placebo in the subgroup of participants with programmed cell death-ligand 1 (PD-L1)-positive tumor expression. Participants will be stratified for stage of disease and region and then will be randomly assigned to receive either pembrolizumab or placebo as post-surgery therapy in Part 1. In Part 2, participants who experience a disease recurrence are eligible for pembrolizumab treatment (if treated with placebo in Part 1) or pembrolizumab rechallenge (if treated with pembrolizumab in Part 1).

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: pembrolizumab; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1019 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Melanoma Group
• Actual Study Start Date: Jul 16, 2015
• Actual Primary Completion Date: Jan 8, 2018
• Anticipated Study Completion Date: Jul 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab In Part 1, participants receive pembrolizumab 200 mg intravenously (IV) as post-surgery therapy every 3 weeks (Q3W) for up to 1 year. During Part 2, participants with documented recurrence may receive optional re-treatment with pembrolizumab Q3W for up to 2 years or disease progression.	Biological: pembrolizumab; Pembrolizumab 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle; Other Names: KEYTRUDA® MK-3475
Placebo Comparator: Placebo In Part 1, participants receive placebo IV as post-surgery therapy Q3W. During Part 2, participants with documented recurrence who received placebo in Part 1 may receive optional treatment with pembrolizumab Q3W for up to 2 years or disease progression.	Drug: placebo; Normal saline solution administered IV on Day 1 of each 21-day cycle

Outcome Measures

Primary Outcome Measures

1. Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants [6 months]

   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.

2. Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression [6 months]

   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.

Secondary Outcome Measures

1. Distant Metastases-free Survival (DMFS) in All Participants [Up to 10 years]

   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.

2. Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression [Up to 10 years]

   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.

3. Overall Survival (OS) for All Participants [Up to 10 years]

   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.

4. Overall Survival (OS) for Participants With PD-L1-positive Tumor Expression [Up to 10 years]

   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.

5. Number of Participants Who Experienced At Least 1 Adverse Event (AE) [Up to 22 months]

   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.

6. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [Up to 22 months]

   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.

7. Clearance (CL) of Pembrolizumab [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.]

   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.

8. Volume of Distribution (V) of Pembrolizumab [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.]

   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.

9. Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment [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.]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Completely resected Stage III melanoma

• Tumor tissue available for evaluation of PD-L1 expression

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate organ function

• No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible)

• Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication

• Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication

Exclusion criteria:

• Mucosal or ocular melanoma

• History of (non-infectious) pneumonitis that required steroids or current pneumonitis

• History of or current interstitial lung disease

• History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years

• Active autoimmune disease that has required systemic treatment in past 2 years

• Active infection requiring therapy

• Unstable hyperthyroidism or hypothyroidism

• Diagnosis of immunodeficiency

• Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication

• Known history of human immunodeficiency virus (HIV), active Hepatitis B or C

• Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible

• Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent, or prior participation in any Merck pembrolizumab clinical trial

• Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication

• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication

• Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC
• European Organisation for Research and Treatment of Cancer

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 28, 2018

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02362594
• Other Study ID Numbers: 3475-054; 1325-MG; 2014-004944-37; 163277; KEYNOTE-054; MK-3475-054
• First Posted: Feb 13, 2015
• Last Update Posted: Aug 22, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD-1); Programmed Cell Death 1 (PD1); Programmed Cell Death-Ligand 1 (PD-L1, PDL1); Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
• Additional relevant MeSH terms: Melanoma; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	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 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	264	280
NOT COMPLETED	250	225

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Placebo	Total
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 Participants	514	505	1019
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.9 (13.6)	53.7 (14.2)	53.8 (13.9)
Sex: Female, Male (Count of Participants)
Female	190 37%	201 39.8%	391 38.4%
Male	324 63%	304 60.2%	628 61.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Programmed Death-Ligand 1 (PD-L1) Tumor Status (Count of Participants)
PD-L1 Positive	428 83.3%	425 84.2%	853 83.7%
PD-L1 Negative	59 11.5%	57 11.3%	116 11.4%
Undetermined	27 5.3%	23 4.6%	50 4.9%
Melanoma Stage (Count of Participants)
Stage IIIA (> 1 mm)	80 15.6%	80 15.8%	160 15.7%
Stage IIIB	237 46.1%	230 45.5%	467 45.8%
Stage IIIC (1-3 LN+)	95 18.5%	93 18.4%	188 18.4%
Stage IIIC (≥4 LN+)	102 19.8%	102 20.2%	204 20%
Region of Enrollment (Count of 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%	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 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 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.
Measure Participants	514	505
Number (95% Confidence Interval) [Percentage of Participants]	82.2 16%	73.3 14.5%

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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	One-sided p-value based on log-rank test.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 98.4%; 0.43 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 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.
Measure Participants	428	425
Number (95% Confidence Interval) [Percentage of Participants]	83.8 16.3%	75.4 14.9%

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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	One-sided p-value based on log-rank test.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95.0%; 0.42 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression
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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 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 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.
Measure Participants	509	502
Count of Participants [Participants]	475 92.4%	453 89.7%

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 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 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.
Measure Participants	509	502
Count of Participants [Participants]	70 13.6%	18 3.6%

9. Secondary Outcome

Title	Clearance (CL) of Pembrolizumab
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 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.
Measure Participants	0	0

10. Secondary Outcome

Title	Volume of Distribution (V) of Pembrolizumab
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 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.
Measure Participants	0	0

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 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 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.
Measure Participants	495	0
Negative	473 92%
Non-Treatment emergent positive	5 1%
Treatment emergent positive	17 3.3%

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 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 (%)	# Events	Affected / at Risk (%)	# Events
Total	25/514 (4.9%)		35/505 (6.9%)
Serious Adverse Events
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	128/509 (25.1%)		82/502 (16.3%)
Cardiac disorders
Acute myocardial infarction	1/509 (0.2%)	1	0/502 (0%)	0
Atrial fibrillation	0/509 (0%)	0	1/502 (0.2%)	1
Autoimmune pericarditis	1/509 (0.2%)	2	0/502 (0%)	0
Cardiac failure congestive	1/509 (0.2%)	1	0/502 (0%)	0
Myocarditis	1/509 (0.2%)	1	0/502 (0%)	0
Ventricular tachycardia	1/509 (0.2%)	1	0/502 (0%)	0
Endocrine disorders
Adrenocortical insufficiency acute	1/509 (0.2%)	1	0/502 (0%)	0
Hyperthyroidism	1/509 (0.2%)	1	0/502 (0%)	0
Hypophysitis	3/509 (0.6%)	3	0/502 (0%)	0
Hypopituitarism	1/509 (0.2%)	1	0/502 (0%)	0
Secondary adrenocortical insufficiency	0/509 (0%)	0	1/502 (0.2%)	1
Thyroiditis	2/509 (0.4%)	2	0/502 (0%)	0
Eye disorders
Conjunctivitis allergic	1/509 (0.2%)	1	0/502 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/509 (0%)	0	1/502 (0.2%)	1
Abdominal pain upper	1/509 (0.2%)	1	0/502 (0%)	0
Aptyalism	1/509 (0.2%)	1	0/502 (0%)	0
Autoimmune colitis	3/509 (0.6%)	6	0/502 (0%)	0
Colitis	8/509 (1.6%)	11	0/502 (0%)	0
Constipation	1/509 (0.2%)	1	0/502 (0%)	0
Diarrhoea	5/509 (1%)	9	2/502 (0.4%)	2
Enteritis	1/509 (0.2%)	1	0/502 (0%)	0
Food poisoning	1/509 (0.2%)	1	0/502 (0%)	0
Gastritis	2/509 (0.4%)	3	0/502 (0%)	0
Haemorrhoids	0/509 (0%)	0	1/502 (0.2%)	3
Ileus	1/509 (0.2%)	1	0/502 (0%)	0
Large intestine perforation	1/509 (0.2%)	1	0/502 (0%)	0
Nausea	1/509 (0.2%)	1	0/502 (0%)	0
Oesophageal haemorrhage	0/509 (0%)	0	1/502 (0.2%)	1
Oral lichen planus	1/509 (0.2%)	1	0/502 (0%)	0
Pancreatitis	0/509 (0%)	0	1/502 (0.2%)	1
Pancreatitis acute	1/509 (0.2%)	1	0/502 (0%)	0
Small intestinal perforation	1/509 (0.2%)	1	0/502 (0%)	0
Vomiting	1/509 (0.2%)	1	1/502 (0.2%)	1
General disorders
Discomfort	1/509 (0.2%)	1	0/502 (0%)	0
Fatigue	2/509 (0.4%)	2	0/502 (0%)	0
Granuloma	1/509 (0.2%)	1	0/502 (0%)	0
Oedema	1/509 (0.2%)	1	0/502 (0%)	0
Papillitis	1/509 (0.2%)	1	0/502 (0%)	0
Pyrexia	4/509 (0.8%)	8	0/502 (0%)	0
Systemic inflammatory response syndrome	1/509 (0.2%)	1	0/502 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	2/509 (0.4%)	2	0/502 (0%)	0
Cholecystitis	0/509 (0%)	0	1/502 (0.2%)	1
Cholelithiasis	0/509 (0%)	0	1/502 (0.2%)	1
Hepatitis	2/509 (0.4%)	8	0/502 (0%)	0
Immune system disorders
Anaphylactic reaction	2/509 (0.4%)	2	0/502 (0%)	0
Sarcoidosis	2/509 (0.4%)	2	0/502 (0%)	0
Infections and infestations
Bronchitis	1/509 (0.2%)	1	0/502 (0%)	0
Cellulitis	3/509 (0.6%)	4	7/502 (1.4%)	8
Cholecystitis infective	1/509 (0.2%)	1	0/502 (0%)	0
Diverticulitis	0/509 (0%)	0	1/502 (0.2%)	1
Erysipelas	2/509 (0.4%)	2	4/502 (0.8%)	4
Gastroenteritis viral	1/509 (0.2%)	1	0/502 (0%)	0
Infected seroma	0/509 (0%)	0	2/502 (0.4%)	2
Infection	1/509 (0.2%)	1	0/502 (0%)	0
Lung infection	1/509 (0.2%)	2	0/502 (0%)	0
Pneumonia	1/509 (0.2%)	1	0/502 (0%)	0
Post procedural cellulitis	1/509 (0.2%)	1	0/502 (0%)	0
Respiratory tract infection viral	0/509 (0%)	0	1/502 (0.2%)	1
Skin infection	1/509 (0.2%)	1	1/502 (0.2%)	1
Soft tissue infection	1/509 (0.2%)	2	0/502 (0%)	0
Subcutaneous abscess	1/509 (0.2%)	1	0/502 (0%)	0
Upper respiratory tract infection	0/509 (0%)	0	1/502 (0.2%)	1
Viral infection	1/509 (0.2%)	1	0/502 (0%)	0
Vulvitis	0/509 (0%)	0	1/502 (0.2%)	1
Injury, poisoning and procedural complications
Animal bite	1/509 (0.2%)	1	0/502 (0%)	0
Post procedural haematoma	0/509 (0%)	0	1/502 (0.2%)	1
Spinal column injury	0/509 (0%)	0	1/502 (0.2%)	1
Subarachnoid haemorrhage	0/509 (0%)	0	1/502 (0.2%)	1
Synovial rupture	1/509 (0.2%)	1	0/502 (0%)	0
Wound necrosis	1/509 (0.2%)	1	0/502 (0%)	0
Investigations
Alanine aminotransferase increased	2/509 (0.4%)	3	0/502 (0%)	0
Aspartate aminotransferase increased	3/509 (0.6%)	4	0/502 (0%)	0
Gamma-glutamyltransferase increased	1/509 (0.2%)	1	0/502 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/509 (0.4%)	2	0/502 (0%)	0
Diabetic ketoacidosis	2/509 (0.4%)	2	0/502 (0%)	0
Hypercreatininaemia	1/509 (0.2%)	4	0/502 (0%)	0
Hyperglycaemia	2/509 (0.4%)	5	0/502 (0%)	0
Hyponatraemia	1/509 (0.2%)	2	2/502 (0.4%)	3
Type 1 diabetes mellitus	3/509 (0.6%)	5	0/502 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/509 (0.2%)	1	0/502 (0%)	0
Fasciitis	0/509 (0%)	0	1/502 (0.2%)	1
Intervertebral disc protrusion	1/509 (0.2%)	3	2/502 (0.4%)	2
Myositis	1/509 (0.2%)	2	0/502 (0%)	0
Rheumatoid arthritis	1/509 (0.2%)	1	0/502 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign	0/509 (0%)	0	1/502 (0.2%)	1
Angiolipoma	0/509 (0%)	0	1/502 (0.2%)	1
Basal cell carcinoma	17/509 (3.3%)	24	25/502 (5%)	36
Benign lymph node neoplasm	1/509 (0.2%)	1	0/502 (0%)	0
Benign neoplasm of testis	1/509 (0.2%)	1	0/502 (0%)	0
Bowen's disease	4/509 (0.8%)	4	1/502 (0.2%)	1
Choroid melanoma	0/509 (0%)	0	1/502 (0.2%)	1
Hepatocellular carcinoma	1/509 (0.2%)	1	0/502 (0%)	0
Intracranial tumour haemorrhage	0/509 (0%)	0	1/502 (0.2%)	1
Invasive ductal breast carcinoma	0/509 (0%)	0	1/502 (0.2%)	1
Keratoacanthoma	1/509 (0.2%)	2	0/502 (0%)	0
Lentigo maligna	0/509 (0%)	0	1/502 (0.2%)	1
Leydig cell tumour of the testis	0/509 (0%)	0	1/502 (0.2%)	1
Malignant melanoma	3/509 (0.6%)	3	3/502 (0.6%)	4
Malignant melanoma in situ	1/509 (0.2%)	1	6/502 (1.2%)	6
Mantle cell lymphoma	1/509 (0.2%)	1	0/502 (0%)	0
Melanocytic naevus	1/509 (0.2%)	1	0/502 (0%)	0
Meningioma	1/509 (0.2%)	1	0/502 (0%)	0
Metastases to central nervous system	1/509 (0.2%)	1	1/502 (0.2%)	1
Nodular melanoma	1/509 (0.2%)	2	0/502 (0%)	0
Prostate cancer	1/509 (0.2%)	1	1/502 (0.2%)	1
Rectal adenocarcinoma	0/509 (0%)	0	1/502 (0.2%)	1
Renal cell carcinoma	1/509 (0.2%)	1	1/502 (0.2%)	1
Squamous cell carcinoma	6/509 (1.2%)	10	3/502 (0.6%)	4
Squamous cell carcinoma of skin	1/509 (0.2%)	1	0/502 (0%)	0
Superficial spreading melanoma stage unspecified	0/509 (0%)	0	1/502 (0.2%)	2
Thyroid cancer	1/509 (0.2%)	1	0/502 (0%)	0
Nervous system disorders
Carotid artery aneurysm	0/509 (0%)	0	1/502 (0.2%)	1
Cerebrovascular accident	1/509 (0.2%)	1	0/502 (0%)	0
Dizziness	0/509 (0%)	0	1/502 (0.2%)	1
Facial paralysis	1/509 (0.2%)	1	0/502 (0%)	0
Headache	1/509 (0.2%)	1	0/502 (0%)	0
Myasthenia gravis	1/509 (0.2%)	1	0/502 (0%)	0
Peripheral sensory neuropathy	1/509 (0.2%)	2	0/502 (0%)	0
Sciatica	0/509 (0%)	0	1/502 (0.2%)	1
Transient ischaemic attack	0/509 (0%)	0	1/502 (0.2%)	1
Psychiatric disorders
Anxiety	1/509 (0.2%)	1	1/502 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	1/509 (0.2%)	1	0/502 (0%)	0
Autoimmune nephritis	1/509 (0.2%)	1	0/502 (0%)	0
Glomerulosclerosis	0/509 (0%)	0	1/502 (0.2%)	1
Nephritis	0/509 (0%)	0	1/502 (0.2%)	4
Nephrolithiasis	1/509 (0.2%)	2	0/502 (0%)	0
Renal colic	0/509 (0%)	0	1/502 (0.2%)	1
Tubulointerstitial nephritis	1/509 (0.2%)	1	0/502 (0%)	0
Urinary retention	1/509 (0.2%)	1	0/502 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/509 (0%)	0	1/502 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/509 (0%)	0	1/502 (0.2%)	1
Interstitial lung disease	1/509 (0.2%)	1	0/502 (0%)	0
Pleural effusion	1/509 (0.2%)	1	0/502 (0%)	0
Pneumonitis	7/509 (1.4%)	8	0/502 (0%)	0
Pneumothorax	1/509 (0.2%)	1	0/502 (0%)	0
Pulmonary embolism	2/509 (0.4%)	2	0/502 (0%)	0
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms	1/509 (0.2%)	2	0/502 (0%)	0
Lichenoid keratosis	1/509 (0.2%)	1	0/502 (0%)	0
Psoriasis	1/509 (0.2%)	1	0/502 (0%)	0
Rash	1/509 (0.2%)	1	0/502 (0%)	0
Rash maculo-papular	1/509 (0.2%)	3	0/502 (0%)	0
Urticaria	1/509 (0.2%)	2	0/502 (0%)	0
Surgical and medical procedures
Appendicectomy	1/509 (0.2%)	1	0/502 (0%)	0
Vascular disorders
Deep vein thrombosis	1/509 (0.2%)	1	0/502 (0%)	0
Haematoma	0/509 (0%)	0	1/502 (0.2%)	1
Hypotension	1/509 (0.2%)	1	0/502 (0%)	0
Lymphoedema	1/509 (0.2%)	1	0/502 (0%)	0
Venous thrombosis	0/509 (0%)	0	1/502 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	443/509 (87%)		409/502 (81.5%)
Endocrine disorders
Hyperthyroidism	52/509 (10.2%)	61	6/502 (1.2%)	6
Hypothyroidism	75/509 (14.7%)	93	14/502 (2.8%)	14
Gastrointestinal disorders
Abdominal pain	37/509 (7.3%)	40	31/502 (6.2%)	37
Constipation	34/509 (6.7%)	37	29/502 (5.8%)	32
Diarrhoea	140/509 (27.5%)	238	129/502 (25.7%)	234
Dry mouth	30/509 (5.9%)	32	10/502 (2%)	10
Nausea	88/509 (17.3%)	112	73/502 (14.5%)	103
Vomiting	40/509 (7.9%)	55	22/502 (4.4%)	25
General disorders
Asthenia	56/509 (11%)	93	42/502 (8.4%)	71
Fatigue	168/509 (33%)	247	168/502 (33.5%)	232
Influenza like illness	55/509 (10.8%)	73	38/502 (7.6%)	47
Infections and infestations
Nasopharyngitis	44/509 (8.6%)	54	25/502 (5%)	26
Upper respiratory tract infection	39/509 (7.7%)	49	30/502 (6%)	39
Investigations
Alanine aminotransferase increased	35/509 (6.9%)	41	24/502 (4.8%)	30
Weight decreased	55/509 (10.8%)	69	39/502 (7.8%)	64
Weight increased	63/509 (12.4%)	96	82/502 (16.3%)	117
Metabolism and nutrition disorders
Decreased appetite	36/509 (7.1%)	40	13/502 (2.6%)	15
Musculoskeletal and connective tissue disorders
Arthralgia	79/509 (15.5%)	130	72/502 (14.3%)	98
Back pain	34/509 (6.7%)	37	54/502 (10.8%)	69
Myalgia	35/509 (6.9%)	40	25/502 (5%)	29
Pain in extremity	22/509 (4.3%)	26	30/502 (6%)	34
Nervous system disorders
Dizziness	26/509 (5.1%)	29	31/502 (6.2%)	38
Headache	95/509 (18.7%)	135	93/502 (18.5%)	126
Respiratory, thoracic and mediastinal disorders
Cough	70/509 (13.8%)	88	55/502 (11%)	66
Dyspnoea	46/509 (9%)	50	25/502 (5%)	26
Skin and subcutaneous tissue disorders
Pruritus	99/509 (19.4%)	138	58/502 (11.6%)	74
Rash	67/509 (13.2%)	90	43/502 (8.6%)	51
Rash maculo-papular	27/509 (5.3%)	44	24/502 (4.8%)	26
Vascular disorders
Hypertension	74/509 (14.5%)	178	77/502 (15.3%)	209
Lymphoedema	26/509 (5.1%)	28	36/502 (7.2%)	37

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.