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Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)

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ClinicalTrials.gov Identifier: NCT02578680
Recruitment Status : Active, not recruiting
First Posted : October 19, 2015
Results First Posted : November 28, 2018
Last Update Posted : March 2, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Non-Small-Cell Lung Carcinoma
Interventions Biological: Pembrolizumab 200 mg
Drug: Cisplatin
Drug: Carboplatin
Drug: Pemetrexed
Dietary Supplement: Folic acid 350-1000 μg
Dietary Supplement: Vitamin B12 1000 μg
Drug: Dexamethasone 4 mg
Drug: Saline solution
Enrollment 616
Recruitment Details  
Pre-assignment Details These interim results are based on a database cutoff date of 08-Nov-2017, at which time 372 participants were ongoing in the study. 67 participants randomized to receiving Control treatment had switched to receiving pembrolizumab monotherapy treatment. These interim results are for randomized treatment only.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description Participants received pembrolizumab (pembro) 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Period Title: Overall Study
Started 410 206
Treated 405 202
Switched to Pembrolizumab 0 67
Completed 0 0
Not Completed 410 206
Reason Not Completed
Death             124             104
Protocol Violation             1             1
Withdrawal by Parent/Guardian             1             0
Withdrawal by Subject             8             5
Ongoing in Study             276             96
Arm/Group Title Pembrolizumab Control Total
Hide Arm/Group Description Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression. Total of all reporting groups
Overall Number of Baseline Participants 410 206 616
Hide Baseline Analysis Population Description
The Baseline Analysis Population consisted of all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 410 participants 206 participants 616 participants
63.2  (9.4) 62.8  (9.1) 63.1  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 206 participants 616 participants
Female
156
  38.0%
97
  47.1%
253
  41.1%
Male
254
  62.0%
109
  52.9%
363
  58.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 206 participants 616 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
10
   2.4%
8
   3.9%
18
   2.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
11
   2.7%
3
   1.5%
14
   2.3%
White
387
  94.4%
194
  94.2%
581
  94.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   0.5%
1
   0.5%
3
   0.5%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 206 participants 616 participants
TPS <1%
127
  31.0%
63
  30.6%
190
  30.8%
TPS ≥1%
260
  63.4%
128
  62.1%
388
  63.0%
Not Evaluable
23
   5.6%
15
   7.3%
38
   6.2%
[1]
Measure Description: Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from an archival or newly obtained biopsy. Participants with a TPS ≥1% were classified as PD-L1 positive and participants with a TPS <1% were classified as PD-L1 negative.
Platinum Chemotherapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 206 participants 616 participants
Cisplatin
113
  27.6%
58
  28.2%
171
  27.8%
Carboplatin
297
  72.4%
148
  71.8%
445
  72.2%
[1]
Measure Description: Participants were classified according to the type of platinum chemotherapy the Investigator chose for them to receive: Cisplatin or Carboplatin.
Smoking Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 206 participants 616 participants
Never Smoker
48
  11.7%
25
  12.1%
73
  11.9%
Former/Current Smoker
362
  88.3%
181
  87.9%
543
  88.1%
[1]
Measure Description: Participants were classified according to their smoking status: Never Smoker or Former/Current Smoker.
1.Primary Outcome
Title Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging
Hide Description PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 410 206
Median (95% Confidence Interval)
Unit of Measure: Months
8.8
(7.6 to 9.2)
4.9
(4.7 to 5.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab, Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.00001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.43 to 0.64
Estimation Comments Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.
2.Primary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS is presented.
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 410 206
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
11.3
(8.7 to 15.1)
[1]
NA=Median OS not reached NA=Lower Limit OS not reached NA=Upper Limit OS not reached
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab, Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.00001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.38 to 0.64
Estimation Comments Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.
3.Secondary Outcome
Title Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Hide Description ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 410 206
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
47.6
(42.6 to 52.5)
18.9
(13.8 to 25.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab, Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments H0:Difference in percentages=0 vs H1:Difference in percentages>0
Method Stratified Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage vs. Control
Estimated Value 28.5
Confidence Interval (2-Sided) 95%
21.1 to 35.4
Estimation Comments Miettinen and Nurminen method with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.
4.Secondary Outcome
Title Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Hide Description For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until PD or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented.
Time Frame From time of first documented evidence of CR or PR through database cutoff date of 08-Nov-2017 (Up to approximately 21 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who experienced a confirmed CR or confirmed PR.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 195 39
Median (Full Range)
Unit of Measure: Months
11.2
(1.1 to 18.0)
7.8
(2.1 to 16.4)
5.Secondary Outcome
Title Number of Participants Who Experienced an Adverse Event (AE)
Hide Description An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. For participants who switched from the Control group to receiving pembro, AEs that occurred after the first dose of pembro are excluded from this interim analysis, but will be included in the final analysis. The number of participants who experienced an AE is presented.
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received ≥1 dose of study drug.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 405 202
Measure Type: Count of Participants
Unit of Measure: Participants
404
  99.8%
200
  99.0%
6.Secondary Outcome
Title Number of Participants Who Discontinued Any Study Drug Due to an AE
Hide Description The number of participants who discontinued any randomized study drug due to an AE is presented.
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received ≥1 dose of study drug.
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description:
Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Overall Number of Participants Analyzed 405 202
Measure Type: Count of Participants
Unit of Measure: Participants
112
  27.7%
30
  14.9%
7.Other Pre-specified Outcome
Title Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria
Hide Description [Not Specified]
Time Frame Up to 24 months
Outcome Measure Data Not Reported
Time Frame Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study drug, Other AEs: Up to 30 days after last dose of study drug
Adverse Event Reporting Description Population: All participants receiving ≥1 dose of randomized study drug. Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study drug are excluded as AEs. For participants who switched from the Control group to receiving pembro, AEs occurring after 1st pembro dose are excluded from this interim analysis.
 
Arm/Group Title Pembrolizumab Control
Hide Arm/Group Description Participants received pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembro 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
All-Cause Mortality
Pembrolizumab Control
Affected / at Risk (%) Affected / at Risk (%)
Total   124/405 (30.62%)      105/202 (51.98%)    
Hide Serious Adverse Events
Pembrolizumab Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   202/405 (49.88%)      95/202 (47.03%)    
Blood and lymphatic system disorders     
Anaemia  1  12/405 (2.96%)  13 10/202 (4.95%)  11
Disseminated intravascular coagulation  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Febrile neutropenia  1  23/405 (5.68%)  25 4/202 (1.98%)  4
Leukopenia  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Neutropenia  1  10/405 (2.47%)  10 1/202 (0.50%)  1
Pancytopenia  1  4/405 (0.99%)  4 2/202 (0.99%)  3
Thrombocytopenia  1  13/405 (3.21%)  14 5/202 (2.48%)  5
Cardiac disorders     
Acute myocardial infarction  1  1/405 (0.25%)  2 0/202 (0.00%)  0
Atrial fibrillation  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Atrial flutter  1  0/405 (0.00%)  0 2/202 (0.99%)  2
Cardiac arrest  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Cardiac failure  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Cardiopulmonary failure  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Myocardial infarction  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Pericardial effusion  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pericarditis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Sinus tachycardia  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Stress cardiomyopathy  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Supraventricular tachycardia  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Tachyarrhythmia  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Ventricular arrhythmia  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Endocrine disorders     
Adrenal insufficiency  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Hypothyroidism  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Abdominal pain upper  1  1/405 (0.25%)  1 2/202 (0.99%)  2
Colitis  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Constipation  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Diarrhoea  1  15/405 (3.70%)  17 6/202 (2.97%)  9
Duodenitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Gastroduodenitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Gastrointestinal perforation  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Impaired gastric emptying  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Intestinal ischaemia  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Intestinal pseudo-obstruction  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Intussusception  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Lip oedema  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Mesenteric artery embolism  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Nausea  1  4/405 (0.99%)  4 6/202 (2.97%)  6
Neutropenic colitis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Oesophageal stenosis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Oesophagitis  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Pancreatitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pancreatitis acute  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pancreatitis chronic  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Small intestinal haemorrhage  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Stomatitis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Vomiting  1  8/405 (1.98%)  9 5/202 (2.48%)  5
General disorders     
Asthenia  1  7/405 (1.73%)  7 0/202 (0.00%)  0
Chest pain  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Death  1  3/405 (0.74%)  3 1/202 (0.50%)  1
Fatigue  1  3/405 (0.74%)  3 0/202 (0.00%)  0
General physical health deterioration  1  4/405 (0.99%)  4 2/202 (0.99%)  3
Influenza like illness  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Localised oedema  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Malaise  1  1/405 (0.25%)  1 2/202 (0.99%)  2
Mucosal inflammation  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Multiple organ dysfunction syndrome  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Oedema peripheral  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Pyrexia  1  9/405 (2.22%)  10 3/202 (1.49%)  3
Hepatobiliary disorders     
Autoimmune hepatitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Bile duct stone  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cholangitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cholangitis sclerosing  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cholecystitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Hepatitis  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Hepatotoxicity  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Immune system disorders     
Cytokine release syndrome  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Infections and infestations     
Abdominal sepsis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Bacteraemia  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Bacterial colitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Bronchitis  1  4/405 (0.99%)  4 2/202 (0.99%)  2
CNS ventriculitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cellulitis  1  5/405 (1.23%)  6 1/202 (0.50%)  2
Clostridium difficile colitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Diverticulitis  1  1/405 (0.25%)  2 1/202 (0.50%)  1
Empyema  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Endocarditis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Erysipelas  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Folliculitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Gastroenteritis  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Herpes zoster  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Infected dermal cyst  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Infection  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Infectious pleural effusion  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Influenza  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Kidney infection  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Lower respiratory tract infection  1  2/405 (0.49%)  2 3/202 (1.49%)  3
Lung abscess  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Lung infection  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Neutropenic sepsis  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Oral candidiasis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Otitis media  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Peritonitis  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Pneumocystis jirovecii pneumonia  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pneumonia  1  23/405 (5.68%)  23 17/202 (8.42%)  19
Pneumonia bacterial  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pulmonary sepsis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Respiratory tract infection  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Salmonella bacteraemia  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Sepsis  1  5/405 (1.23%)  5 2/202 (0.99%)  2
Septic shock  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Tuberculosis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Tuberculous pleurisy  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Upper respiratory tract infection  1  6/405 (1.48%)  6 2/202 (0.99%)  5
Urinary tract infection  1  4/405 (0.99%)  4 1/202 (0.50%)  1
Injury, poisoning and procedural complications     
Accidental overdose  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Craniocerebral injury  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Fall  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Femoral neck fracture  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Femur fracture  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Limb traumatic amputation  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Lumbar vertebral fracture  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Spinal compression fracture  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Spinal fracture  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Toxicity to various agents  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Upper limb fracture  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Investigations     
Alanine aminotransferase increased  1  0/405 (0.00%)  0 2/202 (0.99%)  2
Blood calcium decreased  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Blood creatinine increased  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Blood magnesium decreased  1  1/405 (0.25%)  1 0/202 (0.00%)  0
C-reactive protein increased  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Hepatic enzyme increased  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Platelet count decreased  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1  5/405 (1.23%)  6 2/202 (0.99%)  2
Hyperglycaemia  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Hypokalaemia  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Hypomagnesaemia  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Hyponatraemia  1  1/405 (0.25%)  1 2/202 (0.99%)  2
Type 1 diabetes mellitus  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Type 2 diabetes mellitus  1  2/405 (0.49%)  3 0/202 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthralgia  1  5/405 (1.23%)  5 0/202 (0.00%)  0
Back pain  1  1/405 (0.25%)  1 1/202 (0.50%)  2
Flank pain  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Groin pain  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Hypertrophic osteoarthropathy  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Muscle haemorrhage  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Muscular weakness  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Musculoskeletal chest pain  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Myalgia  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pain in extremity  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Pathological fracture  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain  1  3/405 (0.74%)  3 2/202 (0.99%)  2
Malignant neoplasm progression  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Metastases to central nervous system  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Thyroid cancer  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Tracheal neoplasm  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Tumour pain  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Nervous system disorders     
Balance disorder  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Brain stem infarction  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cerebral haemorrhage  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Cerebral infarction  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Cerebrovascular accident  1  3/405 (0.74%)  3 0/202 (0.00%)  0
Dizziness  1  4/405 (0.99%)  4 1/202 (0.50%)  1
Encephalopathy  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Haemorrhage intracranial  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Hydrocephalus  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Ischaemic stroke  1  2/405 (0.49%)  3 1/202 (0.50%)  1
Lacunar stroke  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Lumbar radiculopathy  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Partial seizures  1  0/405 (0.00%)  0 1/202 (0.50%)  2
Seizure  1  2/405 (0.49%)  2 1/202 (0.50%)  1
Syncope  1  2/405 (0.49%)  2 2/202 (0.99%)  2
Transient ischaemic attack  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Vasculitis cerebral  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Product Issues     
Device dislocation  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Psychiatric disorders     
Anxiety  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Confusional state  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Delirium  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Disorientation  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Major depression  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  8/405 (1.98%)  8 0/202 (0.00%)  0
Acute prerenal failure  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Autoimmune nephritis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Haematuria  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Nephritis  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Prerenal failure  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Renal failure  1  1/405 (0.25%)  1 2/202 (0.99%)  2
Renal tubular necrosis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Tubulointerstitial nephritis  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Urinary tract obstruction  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Reproductive system and breast disorders     
Balanoposthitis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Atelectasis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Chronic obstructive pulmonary disease  1  4/405 (0.99%)  5 3/202 (1.49%)  3
Dyspnoea  1  5/405 (1.23%)  5 5/202 (2.48%)  6
Epistaxis  1  1/405 (0.25%)  1 1/202 (0.50%)  1
Haemoptysis  1  3/405 (0.74%)  3 2/202 (0.99%)  2
Haemothorax  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Hiccups  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Obstructive airways disorder  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pleural effusion  1  6/405 (1.48%)  7 4/202 (1.98%)  4
Pneumonia aspiration  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Pneumonitis  1  12/405 (2.96%)  13 4/202 (1.98%)  4
Pneumothorax  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Pulmonary embolism  1  5/405 (1.23%)  5 4/202 (1.98%)  4
Respiratory failure  1  1/405 (0.25%)  1 3/202 (1.49%)  3
Skin and subcutaneous tissue disorders     
Dermatitis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Diabetic foot  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Rash  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Rash papular  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Skin sensitisation  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Vascular disorders     
Deep vein thrombosis  1  2/405 (0.49%)  2 2/202 (0.99%)  2
Hypertension  1  2/405 (0.49%)  2 0/202 (0.00%)  0
Jugular vein thrombosis  1  0/405 (0.00%)  0 1/202 (0.50%)  1
Peripheral artery occlusion  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Vena cava thrombosis  1  1/405 (0.25%)  1 0/202 (0.00%)  0
Venous occlusion  1  0/405 (0.00%)  0 1/202 (0.50%)  1
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pembrolizumab Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   393/405 (97.04%)      196/202 (97.03%)    
Blood and lymphatic system disorders     
Anaemia  1  178/405 (43.95%)  227 88/202 (43.56%)  112
Leukopenia  1  23/405 (5.68%)  26 13/202 (6.44%)  17
Neutropenia  1  104/405 (25.68%)  192 48/202 (23.76%)  91
Thrombocytopenia  1  64/405 (15.80%)  100 25/202 (12.38%)  36
Endocrine disorders     
Hypothyroidism  1  26/405 (6.42%)  34 5/202 (2.48%)  5
Eye disorders     
Lacrimation increased  1  69/405 (17.04%)  76 22/202 (10.89%)  23
Gastrointestinal disorders     
Abdominal pain  1  29/405 (7.16%)  37 11/202 (5.45%)  11
Abdominal pain upper  1  24/405 (5.93%)  26 2/202 (0.99%)  2
Constipation  1  139/405 (34.32%)  199 64/202 (31.68%)  83
Diarrhoea  1  115/405 (28.40%)  156 40/202 (19.80%)  50
Dyspepsia  1  24/405 (5.93%)  29 11/202 (5.45%)  11
Nausea  1  223/405 (55.06%)  392 101/202 (50.00%)  180
Stomatitis  1  35/405 (8.64%)  44 15/202 (7.43%)  20
Vomiting  1  94/405 (23.21%)  160 43/202 (21.29%)  66
General disorders     
Asthenia  1  77/405 (19.01%)  121 49/202 (24.26%)  80
Chest pain  1  34/405 (8.40%)  38 11/202 (5.45%)  13
Fatigue  1  164/405 (40.49%)  258 77/202 (38.12%)  126
Mucosal inflammation  1  35/405 (8.64%)  45 15/202 (7.43%)  22
Oedema peripheral  1  78/405 (19.26%)  106 26/202 (12.87%)  35
Pyrexia  1  74/405 (18.27%)  97 27/202 (13.37%)  40
Infections and infestations     
Conjunctivitis  1  31/405 (7.65%)  40 17/202 (8.42%)  31
Nasopharyngitis  1  30/405 (7.41%)  40 10/202 (4.95%)  12
Upper respiratory tract infection  1  35/405 (8.64%)  41 14/202 (6.93%)  15
Urinary tract infection  1  28/405 (6.91%)  40 11/202 (5.45%)  16
Investigations     
Alanine aminotransferase increased  1  49/405 (12.10%)  62 17/202 (8.42%)  21
Aspartate aminotransferase increased  1  38/405 (9.38%)  49 13/202 (6.44%)  14
Blood creatinine increased  1  46/405 (11.36%)  69 16/202 (7.92%)  24
Weight decreased  1  37/405 (9.14%)  40 15/202 (7.43%)  16
White blood cell count decreased  1  26/405 (6.42%)  45 13/202 (6.44%)  20
Metabolism and nutrition disorders     
Decreased appetite  1  114/405 (28.15%)  149 61/202 (30.20%)  79
Hyperglycaemia  1  27/405 (6.67%)  45 6/202 (2.97%)  9
Hypokalaemia  1  43/405 (10.62%)  70 14/202 (6.93%)  17
Hypomagnesaemia  1  31/405 (7.65%)  43 8/202 (3.96%)  13
Hypophosphataemia  1  21/405 (5.19%)  29 5/202 (2.48%)  7
Musculoskeletal and connective tissue disorders     
Arthralgia  1  33/405 (8.15%)  43 17/202 (8.42%)  20
Back pain  1  52/405 (12.84%)  61 22/202 (10.89%)  23
Musculoskeletal pain  1  25/405 (6.17%)  32 17/202 (8.42%)  19
Pain in extremity  1  29/405 (7.16%)  32 17/202 (8.42%)  17
Nervous system disorders     
Dizziness  1  45/405 (11.11%)  48 18/202 (8.91%)  19
Dysgeusia  1  46/405 (11.36%)  52 19/202 (9.41%)  20
Headache  1  48/405 (11.85%)  57 19/202 (9.41%)  23
Paraesthesia  1  20/405 (4.94%)  27 12/202 (5.94%)  18
Psychiatric disorders     
Insomnia  1  24/405 (5.93%)  29 14/202 (6.93%)  14
Respiratory, thoracic and mediastinal disorders     
Cough  1  87/405 (21.48%)  112 57/202 (28.22%)  63
Dyspnoea  1  82/405 (20.25%)  98 47/202 (23.27%)  57
Epistaxis  1  29/405 (7.16%)  35 7/202 (3.47%)  11
Haemoptysis  1  11/405 (2.72%)  13 14/202 (6.93%)  15
Oropharyngeal pain  1  21/405 (5.19%)  24 4/202 (1.98%)  4
Productive cough  1  21/405 (5.19%)  24 11/202 (5.45%)  12
Rhinorrhoea  1  22/405 (5.43%)  24 9/202 (4.46%)  9
Skin and subcutaneous tissue disorders     
Alopecia  1  21/405 (5.19%)  22 9/202 (4.46%)  9
Dry skin  1  18/405 (4.44%)  19 18/202 (8.91%)  18
Erythema  1  21/405 (5.19%)  24 4/202 (1.98%)  5
Pruritus  1  43/405 (10.62%)  55 21/202 (10.40%)  22
Rash  1  81/405 (20.00%)  108 23/202 (11.39%)  28
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT02578680    
Other Study ID Numbers: 3475-189
163421 ( Registry Identifier: JAPIC-CTI )
MK-3475-189 ( Other Identifier: Merck Protocol Number )
2015-003694-15 ( EudraCT Number )
First Submitted: October 15, 2015
First Posted: October 19, 2015
Results First Submitted: September 11, 2018
Results First Posted: November 28, 2018
Last Update Posted: March 2, 2022