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Study of Pembrolizumab With or Without Platinum-based Combination Chemotherapy Versus Chemotherapy Alone in Urothelial Carcinoma (MK-3475-361/KEYNOTE-361)

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ClinicalTrials.gov Identifier: NCT02853305
Recruitment Status : Completed
First Posted : August 2, 2016
Results First Posted : May 20, 2021
Last Update Posted : September 8, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Urothelial Carcinoma Associated 1 RNA, Human
Interventions Biological: Pembrolizumab
Drug: Cisplatin
Drug: Carboplatin
Drug: Gemcitabine
Enrollment 1010
Recruitment Details Participants with advanced or metastatic urothelial carcinoma were recruited to examine the efficacy and safety of pembrolizumab plus chemotherapy (pembro combo) versus pembrolizumab alone (pembro) or chemotherapy alone (chemo).
Pre-assignment Details 1,010 participants were randomized 1:1:1 to receive pembrolizumab plus chemotherapy, pembrolizumab alone, or chemotherapy alone. Per protocol, response/progression or adverse events (AEs) that occurred during the second course were not counted towards efficacy outcome measures or safety outcome measures, respectively.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with SD or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Period Title: Overall Study
Started 351 307 352
Received First Course of Pembrolizumab 349 [1] 302 342
Received Second Course of Pembrolizumab 14 15 0
Completed 0 0 0
Not Completed 351 307 352
Reason Not Completed
Death             287             249             300
Withdrawal by Subject             2             8             3
Transferred to Extension Study             46             30             25
Did Not Continue on Extension Study             16             20             24
[1]
Includes 2 participants randomized to Pembrolizumab alone
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo) Total
Hide Arm/Group Description Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with SD or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Total of all reporting groups
Overall Number of Baseline Participants 351 307 352 1010
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 351 participants 307 participants 352 participants 1010 participants
68.3  (9.2) 67.0  (10.1) 68.0  (9.6) 67.8  (9.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 351 participants 307 participants 352 participants 1010 participants
Female
79
  22.5%
79
  25.7%
90
  25.6%
248
  24.6%
Male
272
  77.5%
228
  74.3%
262
  74.4%
762
  75.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 351 participants 307 participants 352 participants 1010 participants
Hispanic or Latino
26
   7.4%
25
   8.1%
32
   9.1%
83
   8.2%
Not Hispanic or Latino
269
  76.6%
231
  75.2%
261
  74.1%
761
  75.3%
Unknown or Not Reported
56
  16.0%
51
  16.6%
59
  16.8%
166
  16.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 351 participants 307 participants 352 participants 1010 participants
American Indian or Alaska Native
0
   0.0%
1
   0.3%
0
   0.0%
1
   0.1%
Asian
64
  18.2%
47
  15.3%
70
  19.9%
181
  17.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   0.3%
3
   1.0%
4
   1.1%
8
   0.8%
White
243
  69.2%
212
  69.1%
235
  66.8%
690
  68.3%
More than one race
1
   0.3%
2
   0.7%
1
   0.3%
4
   0.4%
Unknown or Not Reported
42
  12.0%
42
  13.7%
42
  11.9%
126
  12.5%
PD-L1 CPS Status-IVRS   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 351 participants 307 participants 352 participants 1010 participants
PD-L1 CPS<10
192
  54.7%
148
  48.2%
193
  54.8%
533
  52.8%
PD-L1 CPS≥10
159
  45.3%
159
  51.8%
159
  45.2%
477
  47.2%
[1]
Measure Description: The Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by immunohistochemistry (IHC). Higher percentages of PD-L1 CPS staining corresponded to higher positivity of PD-L1 on a tumor. The number of participants with CPS <10% and CPS ≥10% at baseline randomization by Interactive Voice Response System (IVRS) is presented
Investigator Choice of Cisplatin or Carboplatin - IVRS   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 351 participants 307 participants 352 participants 1010 participants
Cisplatin
160
  45.6%
138
  45.0%
160
  45.5%
458
  45.3%
Carboplatin
191
  54.4%
169
  55.0%
192
  54.5%
552
  54.7%
[1]
Measure Description: The Investigator's choice of chemotherapy drug (cisplatin or carboplatin) at baseline randomization by IVRS is presented.
1.Primary Outcome
Title Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
Hide Description

PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, 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. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study.

Per protocol, PFS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population (all randomized participants). PFS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 0 352
Median (95% Confidence Interval)
Unit of Measure: Months
8.3
(7.5 to 8.5)
7.1
(6.4 to 7.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments PFS in all participants of the pembro combo arm was compared to PFS in all participants of the chemo arm to address the first primary hypothesis (superiority to chemo). The hazard ratio (HR) and its 95% confidence interval (CI) were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0033
Comments [Not Specified]
Method Stratified Log-Rank
Comments The treatment difference in PFS was assessed by the stratified log-rank test.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.65 to 0.93
Estimation Comments [Not Specified]
2.Primary Outcome
Title Pembro Combo vs Chemo: 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 final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 0 352
Median (95% Confidence Interval)
Unit of Measure: Months
17.0
(14.5 to 19.5)
14.3
(12.3 to 16.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments OS in all participants of the pembro combo arm was compared to OS in all participants of the chemo arm to address the second primary hypothesis (superiority to chemo). The HR and its 95% CI were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0407
Comments [Not Specified]
Method Stratified Log-Rank
Comments The treatment difference in OS was assessed by the stratified log-rank test.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.72 to 1.02
Estimation Comments [Not Specified]
3.Primary Outcome
Title Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%
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 final analysis were censored at the date of the last follow-up. Per protocol, OS in the CPS ≥10% subset of the pembro arm was compared to OS in the CPS ≥10% subset of the chemo arm for this endpoint as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro arm and chemo arm who were PD-L1 CPS ≥10%. Per protocol, OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of the ITT population and is not presented.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm who were PD-L1 CPS ≥10% were included in the analysis. Per protocol, the pembro combo arm was not pre-specified as part of this analysis and is not included.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 160 158
Median (95% Confidence Interval)
Unit of Measure: Months
16.1
(13.6 to 19.9)
15.2
(11.6 to 23.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments OS in CPS≥10 participants of the pembro arm was compared to OS in CPS≥10 participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.77 to 1.32
Estimation Comments [Not Specified]
4.Primary Outcome
Title Pembro vs Chemo: 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 final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 307 352
Median (95% Confidence Interval)
Unit of Measure: Months
15.6
(12.1 to 17.9)
14.3
(12.3 to 16.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments OS in all participants of the pembro arm was compared to OS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.77 to 1.11
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study.

Per protocol, PFS in the pembro arm was compared to the chemo arm as a pre-specified analysis of the ITT population (all randomized participants). PFS is reported here for all participants in the pembro arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 307 352
Median (95% Confidence Interval)
Unit of Measure: Months
3.9
(2.3 to 5.1)
7.1
(6.4 to 7.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments PFS in all participants of the pembro arm was compared to PFS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.32
Confidence Interval (2-Sided) 95%
1.09 to 1.58
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants Who Experience an Adverse Event (AE)
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm.
Time Frame Up to approximately 55 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of trial treatment were analyzed.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 349 302 342
Measure Type: Count of Participants
Unit of Measure: Participants
348
  99.7%
289
  95.7%
341
  99.7%
7.Secondary Outcome
Title Number of Participants Who Discontinue Study Drug Due to an AE
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm.
Time Frame Up to approximately 52 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of trial treatment were analyzed.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 349 302 342
Measure Type: Count of Participants
Unit of Measure: Participants
108
  30.9%
48
  15.9%
62
  18.1%
8.Secondary Outcome
Title Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR
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) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 0 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
54.7
(49.3 to 60.0)
44.9
(39.6 to 50.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments ORR in participants of the pembro combo arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen & Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value 9.8
Confidence Interval (2-Sided) 95%
2.4 to 17.1
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR
Hide Description For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro combo arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro arm and chemo arm and is presented later in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm and who demonstrated a confirmed CR or PR were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 192 0 158
Median (95% Confidence Interval)
Unit of Measure: Months
8.5
(8.2 to 11.4)
6.2
(5.8 to 6.6)
10.Secondary Outcome
Title Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR
Hide Description DCR was defined as the percentage of participants who had a confirmed CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD]). Per protocol, DCR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro combo arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 0 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
80.3
(75.8 to 84.4)
75.9
(71.0 to 80.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments DCR in participants of the pembro combo arm was compared to DCR in participants of the chemo arm based on the Miettinen & Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value 4.5
Confidence Interval (2-Sided) 95%
-1.6 to 10.6
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR
Hide Description ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 307 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
30.3
(25.2 to 35.8)
44.9
(39.6 to 50.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments ORR in participants of the pembro arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen & Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value -14.8
Confidence Interval (2-Sided) 95%
-22.0 to -7.4
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR
Hide Description For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm who demonstrated a confirmed CR or PR were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 93 158
Median (95% Confidence Interval)
Unit of Measure: Months
28.2 [1] 
(13.5 to NA)
6.2
(5.8 to 6.6)
[1]
NA= DOR upper 95% confidence limit undefined because the DOR rate was not low enough at the time of the cut-off date
13.Secondary Outcome
Title Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR
Hide Description DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD]). Per protocol, DCR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 307 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
47.2
(41.5 to 53.0)
75.9
(71.0 to 80.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments DCR in participants of the pembro arm was compared to DCR in participants of the chemo arm based on the Miettinen & Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value -28.9
Confidence Interval (2-Sided) 95%
-35.9 to -21.6
Estimation Comments [Not Specified]
14.Secondary Outcome
Title PFS Using RECIST 1.1 as Assessed by BICR at 6 Months
Hide Description PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 6 months based on the product-limit (Kaplan-Meier) method for censored data.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population (all randomized) were analyzed.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 307 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
73.7
(68.6 to 78.0)
43.6
(37.9 to 49.1)
70.3
(64.8 to 75.0)
15.Secondary Outcome
Title PFS Using RECIST 1.1 as Assessed by BICR at 12 Months
Hide Description PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 12 months based on the product-limit (Kaplan-Meier) method for censored data.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population (all randomized) were analyzed.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 307 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
33.7
(28.6 to 38.9)
26.6
(21.6 to 31.9)
20.9
(16.0 to 26.1)
16.Secondary Outcome
Title PFS Using RECIST 1.1 as Assessed by BICR at 18 Months
Hide Description PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 18 months based on the product-limit (Kaplan-Meier) method for censored data.
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population (all randomized) were analyzed.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 351 307 352
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
23.0
(18.4 to 27.8)
19.1
(14.7 to 24.0)
13.5
(9.3 to 18.4)
17.Secondary Outcome
Title Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Hide Description The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time Frame Baseline, Week 18
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm who received at least 1 dose of study drug and who completed at least 1 EORTC-QLQ-C30 assessment were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and is not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 336 0 337
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
2.54
(-0.08 to 5.16)
-0.14
(-2.91 to 2.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator's choice of chemotherapy [cisplatin or carboplatin] and PD-L1 status [CPS<10 vs. CPS≥10]) at baseline as covariates.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS Means
Estimated Value 2.68
Confidence Interval (2-Sided) 95%
-0.76 to 6.12
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
Hide Description EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro combo arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro arm and chemo arm and is presented later in the record.
Time Frame Baseline up to approximately 25 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro combo arm and chemo arm who received at least 1 dose of study drug and who had an EORTC-QLQ-C30 assessment at baseline were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and is not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 314 0 311
Median (95% Confidence Interval)
Unit of Measure: Months
8.0
(5.9 to 10.3)
4.5
(2.8 to 8.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + ST Chemotherapy (Pembro Combo), ST Chemotherapy (Chemo)
Comments TTD in GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.62 to 1.00
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score
Hide Description The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Baseline, Week 18
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm who received at least 1 dose of study drug and who completed at least 1 EORTC-QLQ-C30 assessment were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and is not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 301 337
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
-1.89
(-5.04 to 1.26)
-0.95
(-3.95 to 2.06)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm. Comparison based on cLDA model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator's choice of chemotherapy [cisplatin or carboplatin] and PD-L1 status [CPS<10 vs. CPS≥10]) at baseline as covariates.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS Means
Estimated Value -0.94
Confidence Interval (2-Sided) 95%
-5.06 to 3.18
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
Hide Description EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro combo arm and chemo arm and is presented earlier in the record.
Time Frame Baseline up to approximately 25 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to the pembro arm and chemo arm who received at least 1 dose of study drug and who had an EORTC-QLQ-C30 assessment at baseline were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and is not included in this analysis.
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.
Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
Overall Number of Participants Analyzed 0 275 311
Median (95% Confidence Interval)
Unit of Measure: Months
3.6
(2.1 to 5.2)
4.5
(2.8 to 8.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab (Pembro), ST Chemotherapy (Chemo)
Comments TTD in GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.18
Confidence Interval (2-Sided) 95%
0.93 to 1.49
Estimation Comments [Not Specified]
Time Frame Up to approximately 70 months
Adverse Event Reporting Description All-Cause Mortality reported for all randomized participants by course. Serious and Other AEs include all treated participants according to treatment received. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug excluded as AEs.
 
Arm/Group Title Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course ST Chemotherapy (Chemo) First Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course Pembrolizumab (Pembro) Second Course
Hide Arm/Group Description Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for a maximum of 35 doses PLUS ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for a maximum of 35 doses. Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped the initial course of pembrolizumab (200 mg IV Q3W for up to 35 treatments [approximately 2 years]) administered in combination with ST chemotherapy, and experienced Stable Disease (SD) or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (up to approximately 1 additional year). Eligible participants who stopped the initial course of pembrolizumab (200 mg IV Q3W for up to 35 treatments [approximately 2 years]) with SD or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (up to approximately 1 additional year).
All-Cause Mortality
Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course ST Chemotherapy (Chemo) First Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course Pembrolizumab (Pembro) Second Course
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   283/351 (80.63%)      244/307 (79.48%)      300/352 (85.23%)      4/14 (28.57%)      8/15 (53.33%)    
Hide Serious Adverse Events
Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course ST Chemotherapy (Chemo) First Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course Pembrolizumab (Pembro) Second Course
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   189/349 (54.15%)      145/302 (48.01%)      138/342 (40.35%)      0/14 (0.00%)      0/15 (0.00%)    
Blood and lymphatic system disorders           
Anaemia † 1  15/349 (4.30%)  15 6/302 (1.99%)  8 19/342 (5.56%)  19 0/14 (0.00%)  0 0/15 (0.00%)  0
Disseminated intravascular coagulation † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Febrile neutropenia † 1  9/349 (2.58%)  9 0/302 (0.00%)  0 11/342 (3.22%)  11 0/14 (0.00%)  0 0/15 (0.00%)  0
Haematotoxicity † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Leukopenia † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Neutropenia † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Pancytopenia † 1  10/349 (2.87%)  10 0/302 (0.00%)  0 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Thrombocytopenia † 1  12/349 (3.44%)  15 0/302 (0.00%)  0 10/342 (2.92%)  11 0/14 (0.00%)  0 0/15 (0.00%)  0
Thrombotic thrombocytopenic purpura † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac disorders           
Acute coronary syndrome † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Acute myocardial infarction † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Angina pectoris † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Aortic valve stenosis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Arrhythmia † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Atrial fibrillation † 1  4/349 (1.15%)  4 2/302 (0.66%)  2 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac arrest † 1  3/349 (0.86%)  3 2/302 (0.66%)  2 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac failure † 1  0/349 (0.00%)  0 5/302 (1.66%)  5 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac failure acute † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac failure chronic † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiac failure congestive † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardio-respiratory arrest † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cardiomyopathy † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Coronary artery disease † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Left ventricular dysfunction † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Left ventricular failure † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Myocardial infarction † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Myocardial ischaemia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Myocarditis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Congenital, familial and genetic disorders           
Dolichocolon † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Odontogenic cyst † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Endocrine disorders           
Adrenocortical insufficiency acute † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Adrenocorticotropic hormone deficiency † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypercalcaemia of malignancy † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypophysitis † 1  2/349 (0.57%)  2 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypopituitarism † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypothyroidism † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Thyroiditis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Eye disorders           
Cataract † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Diplopia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Epiretinal membrane † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastrointestinal disorders           
Abdominal pain † 1  3/349 (0.86%)  3 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Anal fistula † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Ascites † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Autoimmune colitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Colitis † 1  2/349 (0.57%)  2 2/302 (0.66%)  4 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Colitis ischaemic † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Constipation † 1  2/349 (0.57%)  2 3/302 (0.99%)  3 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Diarrhoea † 1  3/349 (0.86%)  4 5/302 (1.66%)  5 4/342 (1.17%)  4 0/14 (0.00%)  0 0/15 (0.00%)  0
Enterocolitis haemorrhagic † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Enterocolonic fistula † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastrointestinal fistula † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastrointestinal haemorrhage † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Haematochezia † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Haemorrhoidal haemorrhage † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Ileus † 1  1/349 (0.29%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Inguinal hernia † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Intestinal obstruction † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Large intestinal obstruction † 1  2/349 (0.57%)  2 1/302 (0.33%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Mechanical ileus † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Melaena † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Nausea † 1  1/349 (0.29%)  1 1/302 (0.33%)  2 4/342 (1.17%)  4 0/14 (0.00%)  0 0/15 (0.00%)  0
Pancreatitis † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Rectal ulcer † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Short-bowel syndrome † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Small intestinal obstruction † 1  1/349 (0.29%)  1 3/302 (0.99%)  3 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Subileus † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Upper gastrointestinal haemorrhage † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Vomiting † 1  3/349 (0.86%)  3 0/302 (0.00%)  0 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
General disorders           
Asthenia † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Death † 1  6/349 (1.72%)  6 3/302 (0.99%)  3 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Fatigue † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Gait disturbance † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
General physical health deterioration † 1  3/349 (0.86%)  3 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypothermia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Inflammation † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Influenza like illness † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Malaise † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Medical device site laceration † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Mucosal inflammation † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Multiple organ dysfunction syndrome † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Oedema peripheral † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pyrexia † 1  6/349 (1.72%)  7 3/302 (0.99%)  3 4/342 (1.17%)  4 0/14 (0.00%)  0 0/15 (0.00%)  0
Sudden death † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatobiliary disorders           
Acute hepatic failure † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Autoimmune hepatitis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cholecystitis † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cholecystitis acute † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cirrhosis alcoholic † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatic function abnormal † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatotoxicity † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypertransaminasaemia † 1  1/349 (0.29%)  1 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Liver injury † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Immune system disorders           
Anaphylactic reaction † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Drug hypersensitivity † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Sarcoidosis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Infections and infestations           
Abdominal abscess † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Abdominal infection † 1  1/349 (0.29%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Abdominal sepsis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Acute hepatitis B † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Appendicitis perforated † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Bacteraemia † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Bacterial diarrhoea † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Bronchitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
COVID-19 pneumonia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Catheter site infection † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cellulitis † 1  3/349 (0.86%)  3 4/302 (1.32%)  4 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Clostridium difficile colitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cystitis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Dengue fever † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Device related infection † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Device related sepsis † 1  2/349 (0.57%)  3 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Diverticulitis † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Endocarditis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Enterobacter bacteraemia † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Escherichia sepsis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Escherichia urinary tract infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastroenteritis † 1  1/349 (0.29%)  1 2/302 (0.66%)  2 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Herpes zoster † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Influenza † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Intervertebral discitis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lower respiratory tract infection † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lung abscess † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Neutropenic sepsis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Oral candidiasis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Osteomyelitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Parotid abscess † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pelvic abscess † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Periodontitis † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Peritonitis † 1  1/349 (0.29%)  1 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pneumonia † 1  8/349 (2.29%)  8 6/302 (1.99%)  7 6/342 (1.75%)  6 0/14 (0.00%)  0 0/15 (0.00%)  0
Pneumonia aspiration † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pneumonia bacterial † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pseudomembranous colitis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pulmonary sepsis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pyelonephritis † 1  5/349 (1.43%)  5 6/302 (1.99%)  6 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Pyelonephritis acute † 1  4/349 (1.15%)  5 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pyonephrosis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Rash pustular † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Respiratory tract infection † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Scrotal infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Sepsis † 1  3/349 (0.86%)  3 1/302 (0.33%)  2 4/342 (1.17%)  4 0/14 (0.00%)  0 0/15 (0.00%)  0
Septic arthritis staphylococcal † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Septic shock † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Skin bacterial infection † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Skin infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Stoma site infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Urinary tract infection † 1  31/349 (8.88%)  65 19/302 (6.29%)  22 22/342 (6.43%)  28 0/14 (0.00%)  0 0/15 (0.00%)  0
Urinary tract infection bacterial † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Urosepsis † 1  13/349 (3.72%)  15 7/302 (2.32%)  7 7/342 (2.05%)  7 0/14 (0.00%)  0 0/15 (0.00%)  0
Viral infection † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Wound infection † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Injury, poisoning and procedural complications           
Abdominal wound dehiscence † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Femur fracture † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hip fracture † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Joint dislocation † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Joint injury † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lower limb fracture † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lumbar vertebral fracture † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Overdose † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Post procedural complication † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Post procedural discharge † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Post procedural fever † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Post procedural haematoma † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Procedural pneumothorax † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Rib fracture † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Skull fracture † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Spinal compression fracture † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Urethral injury † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Urostomy complication † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Investigations           
Anticoagulation drug level above therapeutic † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Blood creatinine increased † 1  2/349 (0.57%)  3 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Blood potassium increased † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Haemoglobin decreased † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatic enzyme increased † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
International normalised ratio increased † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Liver function test increased † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Neutrophil count decreased † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 7/342 (2.05%)  7 0/14 (0.00%)  0 0/15 (0.00%)  0
Platelet count decreased † 1  11/349 (3.15%)  13 1/302 (0.33%)  1 15/342 (4.39%)  24 0/14 (0.00%)  0 0/15 (0.00%)  0
White blood cell count decreased † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 2/342 (0.58%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Metabolism and nutrition disorders           
Acidosis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Decreased appetite † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Dehydration † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 5/342 (1.46%)  5 0/14 (0.00%)  0 0/15 (0.00%)  0
Diabetes mellitus † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Electrolyte imbalance † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Failure to thrive † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Fluid retention † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Fulminant type 1 diabetes mellitus † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypercalcaemia † 1  3/349 (0.86%)  3 3/302 (0.99%)  3 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyperglycaemia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyperkalaemia † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 1/342 (0.29%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypokalaemia † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyponatraemia † 1  5/349 (1.43%)  5 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Malnutrition † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Type 1 diabetes mellitus † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Musculoskeletal and connective tissue disorders           
Arthralgia † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Back pain † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Chondrocalcinosis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Chondrocalcinosis pyrophosphate † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Gouty arthritis † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Intervertebral disc protrusion † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Musculoskeletal chest pain † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Osteoporosis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pain in extremity † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pathological fracture † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Polyarthritis † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Spinal stenosis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Adenocarcinoma of colon † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Breast cancer † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cancer pain † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lymphangiosis carcinomatosa † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Malignant neoplasm progression † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Prostate cancer † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Tumour pain † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Nervous system disorders           
Cerebral haemorrhage † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Cerebral infarction † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cerebral venous thrombosis † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Cerebrovascular accident † 1  2/349 (0.57%)  3 2/302 (0.66%)  2 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Dementia † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Encephalitis autoimmune † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Headache † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hepatic encephalopathy † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Ischaemic stroke † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Myoclonus † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Polyneuropathy † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Seizure † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Spinal cord compression † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Subarachnoid haemorrhage † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Syncope † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Transient ischaemic attack † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Uraemic encephalopathy † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Product Issues           
Device occlusion † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Psychiatric disorders           
Completed suicide † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Confusional state † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Delirium † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Mental status changes † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Renal and urinary disorders           
Acute kidney injury † 1  17/349 (4.87%)  21 13/302 (4.30%)  15 9/342 (2.63%)  9 0/14 (0.00%)  0 0/15 (0.00%)  0
Autoimmune nephritis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Bladder perforation † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Bladder tamponade † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Chronic kidney disease † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Dysuria † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Haematuria † 1  9/349 (2.58%)  10 14/302 (4.64%)  20 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Hydronephrosis † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Nephropathy † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pollakiuria † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Prerenal failure † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Renal failure † 1  2/349 (0.57%)  2 2/302 (0.66%)  2 5/342 (1.46%)  5 0/14 (0.00%)  0 0/15 (0.00%)  0
Renal impairment † 1  2/349 (0.57%)  2 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Tubulointerstitial nephritis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Ureteric obstruction † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Urethral fistula † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Urinary retention † 1  1/349 (0.29%)  1 5/302 (1.66%)  5 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Urinary tract obstruction † 1  1/349 (0.29%)  1 4/302 (1.32%)  5 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Reproductive system and breast disorders           
Female genital tract fistula † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pelvic pain † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Respiratory, thoracic and mediastinal disorders           
Acute respiratory failure † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Aspiration † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Chronic obstructive pulmonary disease † 1  1/349 (0.29%)  3 1/302 (0.33%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Dyspnoea † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Epistaxis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Haemoptysis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Interstitial lung disease † 1  3/349 (0.86%)  3 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pharyngeal stenosis † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pleural effusion † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pneumonitis † 1  1/349 (0.29%)  1 4/302 (1.32%)  4 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Pneumothorax † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Productive cough † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pulmonary embolism † 1  6/349 (1.72%)  6 3/302 (0.99%)  3 4/342 (1.17%)  4 0/14 (0.00%)  0 0/15 (0.00%)  0
Pulmonary haemorrhage † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pulmonary oedema † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Respiratory failure † 1  2/349 (0.57%)  2 0/302 (0.00%)  0 2/342 (0.58%)  2 0/14 (0.00%)  0 0/15 (0.00%)  0
Skin and subcutaneous tissue disorders           
Angioedema † 1  0/349 (0.00%)  0 0/302 (0.00%)  0 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Dermatitis † 1  1/349 (0.29%)  2 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Dermatitis acneiform † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Drug eruption † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pruritus † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Purpura † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Skin ulcer † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Toxic skin eruption † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Vascular disorders           
Arterial haemorrhage † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Deep vein thrombosis † 1  4/349 (1.15%)  4 3/302 (0.99%)  3 3/342 (0.88%)  3 0/14 (0.00%)  0 0/15 (0.00%)  0
Embolism † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypotension † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypovolaemic shock † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Iliac artery occlusion † 1  1/349 (0.29%)  1 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Lymphoedema † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Orthostatic hypotension † 1  1/349 (0.29%)  1 0/302 (0.00%)  0 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Pelvic venous thrombosis † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Peripheral arterial occlusive disease † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Peripheral ischaemia † 1  0/349 (0.00%)  0 2/302 (0.66%)  2 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
Vascular pain † 1  0/349 (0.00%)  0 1/302 (0.33%)  1 0/342 (0.00%)  0 0/14 (0.00%)  0 0/15 (0.00%)  0
1
Term from vocabulary, MedDRA 25.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course ST Chemotherapy (Chemo) First Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course Pembrolizumab (Pembro) Second Course
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   345/349 (98.85%)      275/302 (91.06%)      337/342 (98.54%)      0/14 (0.00%)      1/15 (6.67%)    
Blood and lymphatic system disorders           
Anaemia † 1  227/349 (65.04%)  334 75/302 (24.83%)  103 210/342 (61.40%)  303 0/14 (0.00%)  0 0/15 (0.00%)  0
Leukopenia † 1  31/349 (8.88%)  60 0/302 (0.00%)  0 25/342 (7.31%)  55 0/14 (0.00%)  0 0/15 (0.00%)  0
Neutropenia † 1  126/349 (36.10%)  274 2/302 (0.66%)  2 129/342 (37.72%)  281 0/14 (0.00%)  0 0/15 (0.00%)  0
Thrombocytopenia † 1  86/349 (24.64%)  175 2/302 (0.66%)  2 89/342 (26.02%)  180 0/14 (0.00%)  0 0/15 (0.00%)  0
Endocrine disorders           
Hypothyroidism † 1  34/349 (9.74%)  43 30/302 (9.93%)  33 1/342 (0.29%)  1 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastrointestinal disorders           
Abdominal pain † 1  41/349 (11.75%)  51 29/302 (9.60%)  35 29/342 (8.48%)  31 0/14 (0.00%)  0 0/15 (0.00%)  0
Abdominal pain upper † 1  12/349 (3.44%)  15 9/302 (2.98%)  11 26/342 (7.60%)  26 0/14 (0.00%)  0 0/15 (0.00%)  0
Constipation † 1  124/349 (35.53%)  155 56/302 (18.54%)  70 107/342 (31.29%)  140 0/14 (0.00%)  0 0/15 (0.00%)  0
Diarrhoea † 1  102/349 (29.23%)  136 58/302 (19.21%)  81 73/342 (21.35%)  91 0/14 (0.00%)  0 0/15 (0.00%)  0
Dyspepsia † 1  14/349 (4.01%)  16 6/302 (1.99%)  6 22/342 (6.43%)  27 0/14 (0.00%)  0 0/15 (0.00%)  0
Gastrooesophageal reflux disease † 1  19/349 (5.44%)  20 1/302 (0.33%)  1 6/342 (1.75%)  7 0/14 (0.00%)  0 0/15 (0.00%)  0
Nausea † 1  180/349 (51.58%)  279 43/302 (14.24%)  53 154/342 (45.03%)  247 0/14 (0.00%)  0 0/15 (0.00%)  0
Stomatitis † 1  22/349 (6.30%)  28 13/302 (4.30%)  14 18/342 (5.26%)  20 0/14 (0.00%)  0 0/15 (0.00%)  0
Vomiting † 1  91/349 (26.07%)  142 33/302 (10.93%)  43 72/342 (21.05%)  108 0/14 (0.00%)  0 0/15 (0.00%)  0
General disorders           
Asthenia † 1  84/349 (24.07%)  138 42/302 (13.91%)  50 84/342 (24.56%)  120 0/14 (0.00%)  0 0/15 (0.00%)  0
Fatigue † 1  147/349 (42.12%)  199 78/302 (25.83%)  94 122/342 (35.67%)  150 0/14 (0.00%)  0 0/15 (0.00%)  0
Malaise † 1  12/349 (3.44%)  13 3/302 (0.99%)  3 20/342 (5.85%)  23 0/14 (0.00%)  0 0/15 (0.00%)  0
Mucosal inflammation † 1  20/349 (5.73%)  23 4/302 (1.32%)  4 9/342 (2.63%)  15 0/14 (0.00%)  0 0/15 (0.00%)  0
Oedema peripheral † 1  47/349 (13.47%)  55 27/302 (8.94%)  34 44/342 (12.87%)  48 0/14 (0.00%)  0 0/15 (0.00%)  0
Pyrexia † 1  77/349 (22.06%)  112 43/302 (14.24%)  58 41/342 (11.99%)  62 0/14 (0.00%)  0 0/15 (0.00%)  0
Infections and infestations           
Nasopharyngitis † 1  19/349 (5.44%)  27 14/302 (4.64%)  20 16/342 (4.68%)  16 0/14 (0.00%)  0 0/15 (0.00%)  0
Upper respiratory tract infection † 1  26/349 (7.45%)  31 10/302 (3.31%)  14 10/342 (2.92%)  10 0/14 (0.00%)  0 0/15 (0.00%)  0
Urinary tract infection † 1  70/349 (20.06%)  109 62/302 (20.53%)  93 48/342 (14.04%)  55 0/14 (0.00%)  0 0/15 (0.00%)  0
Investigations           
Alanine aminotransferase increased † 1  54/349 (15.47%)  106 20/302 (6.62%)  22 21/342 (6.14%)  35 0/14 (0.00%)  0 0/15 (0.00%)  0
Aspartate aminotransferase increased † 1  52/349 (14.90%)  93 21/302 (6.95%)  33 20/342 (5.85%)  23 0/14 (0.00%)  0 0/15 (0.00%)  0
Blood alkaline phosphatase increased † 1  23/349 (6.59%)  31 17/302 (5.63%)  19 11/342 (3.22%)  21 0/14 (0.00%)  0 0/15 (0.00%)  0
Blood creatinine increased † 1  68/349 (19.48%)  105 38/302 (12.58%)  39 39/342 (11.40%)  51 0/14 (0.00%)  0 0/15 (0.00%)  0
Neutrophil count decreased † 1  77/349 (22.06%)  174 2/302 (0.66%)  3 69/342 (20.18%)  152 0/14 (0.00%)  0 0/15 (0.00%)  0
Platelet count decreased † 1  78/349 (22.35%)  159 5/302 (1.66%)  5 79/342 (23.10%)  169 0/14 (0.00%)  0 0/15 (0.00%)  0
Weight decreased † 1  38/349 (10.89%)  43 38/302 (12.58%)  39 22/342 (6.43%)  23 0/14 (0.00%)  0 0/15 (0.00%)  0
White blood cell count decreased † 1  55/349 (15.76%)  136 1/302 (0.33%)  1 51/342 (14.91%)  109 0/14 (0.00%)  0 0/15 (0.00%)  0
Metabolism and nutrition disorders           
Decreased appetite † 1  121/349 (34.67%)  147 72/302 (23.84%)  79 95/342 (27.78%)  122 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyperglycaemia † 1  23/349 (6.59%)  54 14/302 (4.64%)  16 7/342 (2.05%)  14 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyperkalaemia † 1  34/349 (9.74%)  60 24/302 (7.95%)  36 17/342 (4.97%)  22 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypoalbuminaemia † 1  19/349 (5.44%)  28 19/302 (6.29%)  22 7/342 (2.05%)  8 0/14 (0.00%)  0 0/15 (0.00%)  0
Hypokalaemia † 1  33/349 (9.46%)  61 19/302 (6.29%)  28 11/342 (3.22%)  12 0/14 (0.00%)  0 1/15 (6.67%)  1
Hypomagnesaemia † 1  39/349 (11.17%)  53 9/302 (2.98%)  10 24/342 (7.02%)  26 0/14 (0.00%)  0 0/15 (0.00%)  0
Hyponatraemia † 1  31/349 (8.88%)  47 25/302 (8.28%)  36 16/342 (4.68%)  23 0/14 (0.00%)  0 0/15 (0.00%)  0
Musculoskeletal and connective tissue disorders           
Arthralgia † 1  45/349 (12.89%)  70 35/302 (11.59%)  41 24/342 (7.02%)  25 0/14 (0.00%)  0 0/15 (0.00%)  0
Back pain † 1  50/349 (14.33%)  67 37/302 (12.25%)  43 19/342 (5.56%)  22 0/14 (0.00%)  0 0/15 (0.00%)  0
Pain in extremity † 1  32/349 (9.17%)  36 24/302 (7.95%)  27 14/342 (4.09%)  17 0/14 (0.00%)  0 0/15 (0.00%)  0
Nervous system disorders           
Dizziness † 1  45/349 (12.89%)  54 19/302 (6.29%)  23 36/342 (10.53%)  41 0/14 (0.00%)  0 0/15 (0.00%)  0
Dysgeusia † 1  25/349 (7.16%)  28 8/302 (2.65%)  8 28/342 (8.19%)  30 0/14 (0.00%)  0 0/15 (0.00%)  0
Headache † 1  42/349 (12.03%)  52 17/302 (5.63%)  23 27/342 (7.89%)  33 0/14 (0.00%)  0 0/15 (0.00%)  0
Neuropathy peripheral † 1  24/349 (6.88%)  32 2/302 (0.66%)  2 20/342 (5.85%)  23 0/14 (0.00%)  0 0/15 (0.00%)  0
Psychiatric disorders           
Insomnia † 1  35/349 (10.03%)  40 19/302 (6.29%)  19 16/342 (4.68%)  18 0/14 (0.00%)  0 0/15 (0.00%)  0
Renal and urinary disorders           
Acute kidney injury † 1  19/349 (5.44%)  22 9/302 (2.98%)  10 7/342 (2.05%)  10 0/14 (0.00%)  0 0/15 (0.00%)  0
Haematuria † 1  53/349 (15.19%)  66 31/302 (10.26%)  33 18/342 (5.26%)  19 0/14 (0.00%)  0 0/15 (0.00%)  0
Respiratory, thoracic and mediastinal disorders           
Cough † 1  55/349 (15.76%)  65 30/302 (9.93%)  34 28/342 (8.19%)  30 0/14 (0.00%)  0 0/15 (0.00%)  0
Dyspnoea † 1  55/349 (15.76%)  62 34/302 (11.26%)  40 36/342 (10.53%)  40 0/14 (0.00%)  0 0/15 (0.00%)  0
Epistaxis † 1  22/349 (6.30%)  25 3/302 (0.99%)  3 23/342 (6.73%)  31 0/14 (0.00%)  0 0/15 (0.00%)  0
Hiccups † 1  21/349 (6.02%)  29 1/302 (0.33%)  1 14/342 (4.09%)  22 0/14 (0.00%)  0 0/15 (0.00%)  0
Skin and subcutaneous tissue disorders           
Alopecia † 1  26/349 (7.45%)  26 0/302 (0.00%)  0 28/342 (8.19%)  29 0/14 (0.00%)  0 0/15 (0.00%)  0
Dry skin † 1  12/349 (3.44%)  13 18/302 (5.96%)  19 7/342 (2.05%)  7 0/14 (0.00%)  0 0/15 (0.00%)  0
Pruritus † 1  80/349 (22.92%)  109 66/302 (21.85%)  89 17/342 (4.97%)  21 0/14 (0.00%)  0 1/15 (6.67%)  1
Rash † 1  82/349 (23.50%)  108 40/302 (13.25%)  57 24/342 (7.02%)  33 0/14 (0.00%)  0 0/15 (0.00%)  0
Vascular disorders           
Hypertension † 1  23/349 (6.59%)  26 13/302 (4.30%)  17 10/342 (2.92%)  10 0/14 (0.00%)  0 0/15 (0.00%)  0
1
Term from vocabulary, MedDRA 25.0
†
Indicates events were collected by systematic assessment
[Not Specified]
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
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Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme LLC
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT02853305    
Other Study ID Numbers: 3475-361
163458 ( Registry Identifier: JAPIC-CTI )
MK-3475-361 ( Other Identifier: Merck Protocol Number )
2015-005731-41 ( EudraCT Number )
First Submitted: July 29, 2016
First Posted: August 2, 2016
Results First Submitted: April 28, 2021
Results First Posted: May 20, 2021
Last Update Posted: September 8, 2023