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Trial record 1 of 1 for:    keynote-002
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Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01704287
Recruitment Status : Completed
First Posted : October 11, 2012
Results First Posted : March 28, 2017
Last Update Posted : May 18, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Malignant Melanoma
Interventions Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Dacarbazine
Drug: Temozolomide
Enrollment 540
Recruitment Details  
Pre-assignment Details This end of trial analysis is based on a trial closure database cutoff date of 31-Jan-2019.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC) ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg
Hide Arm/Group Description Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Period Title: Initial Treatment Period
Started 180 181 179 0 0
Treated 178 179 171 0 0
Completed 33 47 6 0 0
Not Completed 147 134 173 0 0
Reason Not Completed
Death             139             129             71             0             0
Withdrawal by Subject             3             2             4             0             0
Lost to Follow-up             5             3             0             0             0
Switched to Pembrolizumab             0             0             98             0             0
Period Title: Switch to Pembrolizumab Treatment Period
Started 0 0 0 53 45
Completed 0 0 0 15 7
Not Completed 0 0 0 38 38
Reason Not Completed
Lost to Follow-up             0             0             0             2             1
Death             0             0             0             35             37
Withdrawal by Subject             0             0             0             1             0
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC) Total
Hide Arm/Group Description Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Total of all reporting groups
Overall Number of Baseline Participants 180 181 179 540
Hide Baseline Analysis Population Description
The baseline analysis population consisted of all randomized participants. Participants were included in the group to which they were initially randomized for Baseline Characteristics.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 180 participants 181 participants 179 participants 540 participants
59.5  (14.9) 60.1  (13.3) 60.5  (12.7) 60.1  (13.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 181 participants 179 participants 540 participants
Female
76
  42.2%
72
  39.8%
65
  36.3%
213
  39.4%
Male
104
  57.8%
109
  60.2%
114
  63.7%
327
  60.6%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 181 participants 179 participants 540 participants
PD-L1 Positive
99
  55.0%
97
  53.6%
98
  54.7%
294
  54.4%
PD-L1 Negative
48
  26.7%
46
  25.4%
40
  22.3%
134
  24.8%
Unknown
33
  18.3%
38
  21.0%
41
  22.9%
112
  20.7%
[1]
Measure Description: Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by immunohistochemistry assay and scored on a unique melanoma (Allred Proportion Score [APS]/Melanoma [MEL]) scale of 0 to 5 points. Participants with an APS score of ≥2 (membranous staining in ≥1% of cells) were considered to be PD-L1 Positive and participants with an APS score of 0 or 1 were considered to be PD-L1 Negative.
1.Primary Outcome
Title Progression-free Survival (PFS) - Initial Treatment Period
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 Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 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 have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Median (95% Confidence Interval)
Unit of Measure: Months
2.9
(2.8 to 3.8)
3.0
(2.8 to 5.2)
2.8
(2.6 to 2.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments Cox regression model with treatment as covariate stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); lactate dehydrogenase (LDH) levels (normal vs. elevated LDH levels [≥110% Upper Limit of Normal (ULN)]); & BRAF mutational status (mutant vs. wild-type)
Statistical Test of Hypothesis P-Value <0.0001
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.46 to 0.73
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Statistical Test of Hypothesis P-Value <0.0001
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
0.37 to 0.60
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Statistical Test of Hypothesis P-Value 0.1247
Comments Two-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.66 to 1.05
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
2.Primary Outcome
Title Interim Overall Survival (OS) - Initial Treatment Period
Hide Description OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Median (95% Confidence Interval)
Unit of Measure: Months
13.4
(11.0 to 16.4)
14.7
(11.3 to 19.5)
11.0
(8.9 to 13.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1173
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.67 to 1.10
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0106
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.57 to 0.96
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2905
Comments Two-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.67 to 1.12
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
3.Primary Outcome
Title Final Overall Survival (OS) - Initial Treatment Period
Hide Description OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Time Frame Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Median (95% Confidence Interval)
Unit of Measure: Months
13.4
(11.0 to 16.4)
14.7
(11.3 to 19.5)
11.0
(8.9 to 13.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1146
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.68 to 1.10
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.55 to 0.90
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1490
Comments Two-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.66 to 1.07
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
4.Secondary Outcome
Title Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
Hide Description OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Time Frame Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Median (95% Confidence Interval)
Unit of Measure: Months
PD-L1 Positive Number Analyzed 99 participants 97 participants 98 participants
15.0
(10.9 to 20.9)
17.5
(13.7 to 28.9)
12.1
(7.7 to 18.2)
PD-L1 Negative Number Analyzed 48 participants 46 participants 40 participants
10.5
(6.4 to 13.5)
13.4
(4.6 to 23.3)
9.3
(5.1 to 14.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1-Positive Participants
Statistical Test of Hypothesis P-Value 0.3113
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.66 to 1.28
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1 Positive Participants
Statistical Test of Hypothesis P-Value 0.0208
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.50 to 0.99
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1 Positive Participants
Statistical Test of Hypothesis P-Value 0.0496
Comments Two-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.50 to 1.00
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1 Negative Participants
Statistical Test of Hypothesis P-Value 0.6043
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.65 to 1.76
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1 Negative Participants
Statistical Test of Hypothesis P-Value 0.0335
Comments One-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.37 to 1.04
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
Type of Statistical Test Superiority or Other (legacy)
Comments PD-L1 Negative Participants
Statistical Test of Hypothesis P-Value 0.1504
Comments Two-sided p-value based on stratified log rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.44 to 1.13
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
5.Secondary Outcome
Title Overall Response Rate (ORR) - Initial Treatment Period
Hide Description ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
22.2
(16.4 to 29.0)
27.6
(21.3 to 34.7)
4.5
(1.9 to 8.6)
6.Secondary Outcome
Title Best Overall Response (BOR) - Initial Treatment Period
Hide Description BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
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Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 180 181 179
Measure Type: Number
Unit of Measure: Percentage of Participants
Complete Response 3.3 7.2 0.0
Partial Response 18.9 20.4 4.5
Stable Disease 16.7 14.9 19.0
Progressive Disease 46.7 47.5 61.5
Not Evaluable 13.3 9.9 15.1
No Disease 0.6 0.0 0.0
No Assessment 0.6 0.0 0.0
7.Secondary Outcome
Title Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
Hide Description The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
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Hide Analysis Population Description
The analysis population consisted of all randomized participants in ICC who switched to receiving pembrolizumab. Participants were included in the treatment group to which they were re-randomized (switched) for this efficacy analysis.
Arm/Group Title ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg
Hide Arm/Group Description:
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 53 45
Measure Type: Number
Unit of Measure: Percentage of Participants
Complete Response 1.9 4.4
Partial Response 17.0 13.3
Stable Disease 15.1 11.1
Progressive Disease 54.7 55.6
Not Evaluable 11.3 13.3
No Assessment 0.0 2.2
8.Secondary Outcome
Title Duration of Response (DOR) - Initial Treatment Period
Hide Description For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [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 CR or PR until disease progression 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. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Time Frame Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
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Hide Analysis Population Description
The analysis population consisted of all randomized participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 40 50 8
Median (Full Range)
Unit of Measure: Months
22.8
(1.4 to 25.3)
NA [1] 
(1.1 to NA)
6.8
(2.8 to 11.3)
[1]
NA=DOR Median not reached NA=DOR Upper Limit not reached: no progressive disease by time of last assessment
9.Secondary Outcome
Title Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
Hide Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Time Frame Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
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Hide Analysis Population Description
The analysis population consisted of all participants who received at least one dose of study drug.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC Only ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 178 179 73 53 45 53 45
Measure Type: Count of Participants
Unit of Measure: Participants
172
  96.6%
179
 100.0%
71
  97.3%
52
  98.1%
45
 100.0%
53
 100.0%
41
  91.1%
10.Secondary Outcome
Title Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
Hide Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Time Frame Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
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Hide Analysis Population Description
The analysis population consisted of all participants who received at least one dose of study drug.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC Only ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Hide Arm/Group Description:
Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Overall Number of Participants Analyzed 178 179 73 53 45 53 45
Measure Type: Count of Participants
Unit of Measure: Participants
29
  16.3%
33
  18.4%
13
  17.8%
1
   1.9%
1
   2.2%
4
   7.5%
4
   8.9%
Time Frame Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Adverse Event Reporting Description Safety Population: All participants who received ≥1 dose of study drug. Per protocol, disease progression of cancer under study was not considered an AE unless considered related to study drug. Therefore, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
 
Arm/Group Title Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Hide Arm/Group Description Participants received 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the final analysis. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Participants who were initiall randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
All-Cause Mortality
Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   71/73 (97.26%)      0/53 (0.00%)      0/45 (0.00%)      139/178 (78.09%)      129/179 (72.07%)      35/53 (66.04%)      37/45 (82.22%)    
Hide Serious Adverse Events
Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   33/73 (45.21%)      15/53 (28.30%)      9/45 (20.00%)      91/178 (51.12%)      78/179 (43.58%)      18/53 (33.96%)      18/45 (40.00%)    
Blood and lymphatic system disorders               
Anaemia  1  3/73 (4.11%)  3 1/53 (1.89%)  1 0/45 (0.00%)  0 7/178 (3.93%)  7 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Febrile neutropenia  1  2/73 (2.74%)  2 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Leukopenia  1  1/73 (1.37%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Neutropenia  1  1/73 (1.37%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Thrombocytopenia  1  2/73 (2.74%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Cardiac disorders               
Atrial fibrillation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Atrioventricular block complete  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Cardiac failure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cardiac ventricular disorder  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cardiogenic shock  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Myocardial infarction  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Pericardial effusion  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Ear and labyrinth disorders               
Vertigo positional  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Endocrine disorders               
Adrenal insufficiency  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Addison's disease  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Adrenocortical insufficiency acute  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hyperparathyroidism  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypophysitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypopituitarism  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 2/179 (1.12%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0
Secondary adrenocortical insufficiency  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Inappropriate antidiuretic hormone secretion  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Eye disorders               
Eye movement disorder  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Iritis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastrointestinal disorders               
Colitis  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1
Diarrhoea  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 1/178 (0.56%)  1 4/179 (2.23%)  4 1/53 (1.89%)  1 1/45 (2.22%)  1
Dysphagia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Pancreatitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  2 1/53 (1.89%)  1 0/45 (0.00%)  0
Rectal haemorrhage  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Small intestinal obstruction  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1
Abdominal pain  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 4/179 (2.23%)  4 0/53 (0.00%)  0 0/45 (0.00%)  0
Ascites  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Autoimmune colitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Constipation  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Diverticular perforation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Diverticulum  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastric disorder  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastrointestinal disorder  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastrointestinal pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Haematemesis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Haematochezia  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Ileus  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 2/179 (1.12%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0
Intestinal obstruction  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Intussusception  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Large intestinal ulcer  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Large intestine perforation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Malabsorption  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Nausea  1  3/73 (4.11%)  3 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Small intestinal perforation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Vomiting  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastritis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Lower gastrointestinal haemorrhage  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 2/45 (4.44%)  2
Gastrointestinal haemorrhage  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
General disorders               
Generalised oedema  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 3/178 (1.69%)  3 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Asthenia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Chest pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Cyst  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Death  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Fatigue  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Gait disturbance  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
General physical health deterioration  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 6/179 (3.35%)  6 0/53 (0.00%)  0 0/45 (0.00%)  0
Infusion site extravasation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Malaise  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Oedema  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Pyrexia  1  1/73 (1.37%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1 3/178 (1.69%)  4 4/179 (2.23%)  5 0/53 (0.00%)  0 0/45 (0.00%)  0
Hepatobiliary disorders               
Autoimmune hepatitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cholangitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cholecystitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 3/178 (1.69%)  3 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hepatic failure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hepatic necrosis  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hyperbilirubinaemia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Bile duct obstruction  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Immune system disorders               
Anaphylactic reaction  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypersensitivity  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cytokine release syndrome  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Infections and infestations               
Clostridium difficile colitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Diverticulitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Pneumonia  1  3/73 (4.11%)  3 0/53 (0.00%)  0 2/45 (4.44%)  2 2/178 (1.12%)  2 3/179 (1.68%)  5 3/53 (5.66%)  3 1/45 (2.22%)  1
Sepsis  1  2/73 (2.74%)  2 1/53 (1.89%)  1 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1
Wound infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Appendicitis perforated  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Bacteraemia  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Bronchitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Candida infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cellulitis  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Cellulitis streptococcal  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Enterocolitis infectious  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Erysipelas  1  1/73 (1.37%)  1 1/53 (1.89%)  1 0/45 (0.00%)  0 2/178 (1.12%)  2 2/179 (1.12%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0
Gastroenteritis viral  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Herpes zoster  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Infected cyst  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Infection  1  2/73 (2.74%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Infectious pleural effusion  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Influenza  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Mastitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Osteomyelitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Pelvic abscess  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Respiratory syncytial virus infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Salmonellosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Septic shock  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Skin infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Soft tissue infection  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Streptococcal sepsis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Urinary tract infection  1  2/73 (2.74%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Viral infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Viral rash  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Viral upper respiratory tract infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Abdominal abscess  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Lung infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Postoperative wound infection  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Urosepsis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Injury, poisoning and procedural complications               
Fall  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Femur fracture  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Fracture displacement  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hip fracture  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Limb injury  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Lower limb fracture  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Radiation necrosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Rib fracture  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Spinal fracture  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Traumatic intracranial haemorrhage  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Accidental overdose  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Investigations               
Alanine aminotransferase increased  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Aspartate aminotransferase increased  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hepatic enzyme increased  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Neutrophil count decreased  1  1/73 (1.37%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Platelet count decreased  1  2/73 (2.74%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
White blood cell count decreased  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Metabolism and nutrition disorders               
Cachexia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Dehydration  1  1/73 (1.37%)  1 1/53 (1.89%)  1 0/45 (0.00%)  0 4/178 (2.25%)  4 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Diabetic metabolic decompensation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypercalcaemia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypocalcaemia  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hyponatraemia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 3/179 (1.68%)  3 0/53 (0.00%)  0 0/45 (0.00%)  0
Hyperglycaemia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Type 1 diabetes mellitus  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Musculoskeletal and connective tissue disorders               
Arthralgia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 2/179 (1.12%)  2 0/53 (0.00%)  0 1/45 (2.22%)  1
Pain in extremity  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Back pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 2/179 (1.12%)  2 0/53 (0.00%)  0 0/45 (0.00%)  0
Groin pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Musculoskeletal pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Neck pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Osteoarthritis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Osteolysis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Spondylolisthesis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cervical spine stenosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Intracranial tumour haemorrhage  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Metastases to central nervous system  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 3/178 (1.69%)  3 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Tumour pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1 1/178 (0.56%)  1 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Basal cell carcinoma  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  3 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cancer pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Colon cancer metastatic  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Intestinal metastasis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Invasive ductal breast carcinoma  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Metastases to lymph nodes  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Metastases to meninges  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Metastasis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Oncologic complication  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Prostate cancer  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Rectal cancer  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Small cell carcinoma  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Squamous cell carcinoma  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Squamous cell carcinoma of skin  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  3 0/53 (0.00%)  0 0/45 (0.00%)  0
Tumour haemorrhage  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Nervous system disorders               
Dizziness  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 1/53 (1.89%)  1 0/45 (0.00%)  0
Hemiparesis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1
Seizure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 1/53 (1.89%)  1 2/45 (4.44%)  2
Syncope  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Aphasia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Ataxia  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Brain oedema  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Cerebrovascular accident  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Encephalopathy  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Epilepsy  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Haemorrhage intracranial  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hemiplegia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Lumbar radiculopathy  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Meningitis noninfective  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Myasthenic syndrome  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Myoclonus  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Neuropathy peripheral  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Paraesthesia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Partial seizures  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Presyncope  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Sciatica  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Spinal cord compression  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Transient ischaemic attack  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Peripheral motor neuropathy  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Product Issues               
Device dislocation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Psychiatric disorders               
Confusional state  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 2/178 (1.12%)  2 3/179 (1.68%)  3 1/53 (1.89%)  1 0/45 (0.00%)  0
Delirium  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Mental status changes  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Renal and urinary disorders               
Acute kidney injury  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Hydronephrosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Postrenal failure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Renal failure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Tubulointerstitial nephritis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Urinary tract obstruction  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Renal impairment  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Reproductive system and breast disorders               
Pelvic pain  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Respiratory, thoracic and mediastinal disorders               
Chronic obstructive pulmonary disease  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 2/178 (1.12%)  2 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Dyspnoea  1  3/73 (4.11%)  3 0/53 (0.00%)  0 1/45 (2.22%)  1 2/178 (1.12%)  2 5/179 (2.79%)  5 1/53 (1.89%)  1 0/45 (0.00%)  0
Pleural effusion  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 1/45 (2.22%)  1
Pulmonary embolism  1  2/73 (2.74%)  2 2/53 (3.77%)  2 0/45 (0.00%)  0 2/178 (1.12%)  2 1/179 (0.56%)  1 1/53 (1.89%)  1 0/45 (0.00%)  0
Cough  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Dyspnoea exertional  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Epistaxis  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Haemoptysis  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  2 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Hypoxia  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Interstitial lung disease  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%) 
Laryngeal inflammation  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Pneumonia aspiration  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Pneumonitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 3/179 (1.68%)  3 0/53 (0.00%)  0 0/45 (0.00%)  0
Pneumothorax  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Pulmonary thrombosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Acute respiratory failure  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Alveolitis allergic  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Skin and subcutaneous tissue disorders               
Lichenoid keratosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Rash maculo-papular  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Skin mass  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Stevens-Johnson syndrome  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Purpura  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
Vascular disorders               
Hypotension  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0
Circulatory collapse  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Deep vein thrombosis  1  0/73 (0.00%)  0 1/53 (1.89%)  1 0/45 (0.00%)  0 1/178 (0.56%)  1 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Lymphoedema  1  1/73 (1.37%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Orthostatic hypotension  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Phlebitis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Poor venous access  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 1/178 (0.56%)  1 0/179 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0
Venous thrombosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 1/179 (0.56%)  1 0/53 (0.00%)  0 0/45 (0.00%)  0
Thrombosis  1  0/73 (0.00%)  0 0/53 (0.00%)  0 0/45 (0.00%)  0 0/178 (0.00%)  0 0/179 (0.00%)  0 0/53 (0.00%)  0 1/45 (2.22%)  1
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   66/73 (90.41%)      52/53 (98.11%)      44/45 (97.78%)      158/178 (88.76%)      176/179 (98.32%)      48/53 (90.57%)      36/45 (80.00%)    
Blood and lymphatic system disorders               
Anaemia  1  21/73 (28.77%)  26 15/53 (28.30%)  25 10/45 (22.22%)  10 30/178 (16.85%)  43 26/179 (14.53%)  31 12/53 (22.64%)  13 8/45 (17.78%)  21
Leukopenia  1  8/73 (10.96%)  8 3/53 (5.66%)  6 4/45 (8.89%)  7 0/178 (0.00%)  0 2/179 (1.12%)  3 0/53 (0.00%)  0 0/45 (0.00%)  0
Neutropenia  1  2/73 (2.74%)  2 7/53 (13.21%)  14 5/45 (11.11%)  8