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Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer

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ClinicalTrials.gov Identifier: NCT02516241
Recruitment Status : Active, not recruiting
First Posted : August 5, 2015
Results First Posted : May 13, 2021
Last Update Posted : March 29, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Urothelial Cancer
Interventions Drug: MEDI4736 (Durvalumab)
Drug: Tremelimumab
Drug: Cisplatin
Drug: Carboplatin
Drug: Gemcitabine
Enrollment 1126
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description MEDI4736 (Durvalumab) + Tremelimumab MEDI4736 (Durvalumab) Standard of Care Chemotherapy Treatment
Period Title: Overall Study
Started 342 346 344
Received Treatment 340 345 313
Completed 0 0 0
Not Completed 342 346 344
Reason Not Completed
Death             255             262             270
Lost to Follow-up             1             1             3
Withdrawal by Subject             2             7             12
participants ongoing at data cut-off             84             76             59
Arm/Group Title Combination Therapy Monotherapy Standard of Care Total
Hide Arm/Group Description MEDI4736 (Durvalumab) + Tremelimumab MEDI4736 (Durvalumab) Standard of Care Chemotherapy Treatment Total of all reporting groups
Overall Number of Baseline Participants 342 346 344 1032
Hide Baseline Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Age (years) Number Analyzed 342 participants 346 participants 344 participants 1032 participants
66.4  (9.60) 66.3  (9.9) 67.0  (9.32) 66.5  (9.60)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age Group (Years) Number Analyzed 342 participants 346 participants 344 participants 1032 participants
<50
19
   5.6%
22
   6.4%
14
   4.1%
55
   5.3%
>= 50 - < 65
118
  34.5%
115
  33.2%
119
  34.6%
352
  34.1%
>= 65 - < 75
132
  38.6%
141
  40.8%
137
  39.8%
410
  39.7%
>= 75
73
  21.3%
68
  19.7%
74
  21.5%
215
  20.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Sex Number Analyzed 342 participants 346 participants 344 participants 1032 participants
Female
86
  25.1%
97
  28.0%
70
  20.3%
253
  24.5%
Male
256
  74.9%
249
  72.0%
274
  79.7%
779
  75.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Ethnicity Number Analyzed 342 participants 346 participants 344 participants 1032 participants
Hispanic or Latino
15
   4.4%
14
   4.0%
17
   4.9%
46
   4.5%
Not Hispanic or Latino
320
  93.6%
329
  95.1%
322
  93.6%
971
  94.1%
Unknown or Not Reported
7
   2.0%
3
   0.9%
5
   1.5%
15
   1.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 342 participants 346 participants 344 participants 1032 participants
White
253
  74.0%
278
  80.3%
260
  75.6%
791
  76.6%
Black or African American
3
   0.9%
3
   0.9%
0
   0.0%
6
   0.6%
Asian
72
  21.1%
60
  17.3%
76
  22.1%
208
  20.2%
Native Hawaiian or other Pacific islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Other
13
   3.8%
4
   1.2%
8
   2.3%
25
   2.4%
Unknown or Not Reported
1
   0.3%
1
   0.3%
0
   0.0%
2
   0.2%
1.Primary Outcome
Title To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set
Hide Description The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 344
Median (95% Confidence Interval)
Unit of Measure: Months
15.1
(13.1 to 18.0)
12.1
(10.9 to 14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0751
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 98.66%
0.688 to 1.063
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
2.Primary Outcome
Title To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set
Hide Description The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 209 207
Median (95% Confidence Interval)
Unit of Measure: Months
14.4
(10.4 to 17.3)
12.1
(10.4 to 15.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3039
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 96.99%
0.695 to 1.139
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
3.Secondary Outcome
Title OS, Full Analysis Set - Durvalumab Monotherapy vs SoC
Hide Description The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 346 344
Median (95% Confidence Interval)
Unit of Measure: Months
13.2
(10.3 to 15)
12.1
(10.9 to 14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8637
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.830 to 1.169
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
4.Secondary Outcome
Title OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC
Hide Description The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 207
Median (95% Confidence Interval)
Unit of Measure: Months
17.9
(14.8 to 24.2)
12.1
(10.4 to 15.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0091
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.589 to 0.928
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
5.Secondary Outcome
Title OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Median (95% Confidence Interval)
Unit of Measure: Months
11.8
(8.9 to 15.8)
10.9
(8.0 to 14.8)
12.2
(10.4 to 14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7599
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.799 to 1.359
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4424
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.692 to 1.175
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
6.Secondary Outcome
Title Alive at 24 Months (OS24), Full Analysis Set
Hide Description Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
39.0
(33.8 to 44.2)
31.5
(26.6 to 36.4)
29.0
(24.2 to 34.0)
7.Secondary Outcome
Title Alive at 24 Months (OS24), PD-L1-High Analysis Set
Hide Description Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
43.7
(36.8 to 50.3)
36.0
(29.5 to 42.6)
29.3
(23.1 to 35.7)
8.Secondary Outcome
Title Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set
Hide Description Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
32.1
(24.5 to 40.0)
24.5
(17.6 to 32.0)
28.6
(21.2 to 36.4)
9.Secondary Outcome
Title PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

Median PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Median (95% Confidence Interval)
Unit of Measure: Months
3.7
(3.4 to 3.8)
2.3
(1.9 to 3.5)
6.7
(5.7 to 7.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2579
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.10
Confidence Interval (2-Sided) 95%
0.931 to 1.304
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.33
Confidence Interval (2-Sided) 95%
1.124 to 1.567
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
10.Secondary Outcome
Title PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Hide Description

Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

Median PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Median (95% Confidence Interval)
Unit of Measure: Months
4.1
(3.6 to 5.7)
2.4
(1.9 to 3.7)
5.8
(5.6 to 7.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2395
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.705 to 1.091
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2431
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.917 to 1.406
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
11.Secondary Outcome
Title PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description

Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

Median PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Median (95% Confidence Interval)
Unit of Measure: Months
2.0
(1.9 to 3.6)
2.0
(1.9 to 3.5)
7.2
(5.7 to 7.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.53
Confidence Interval (2-Sided) 95%
1.177 to 1.990
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6236
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.729 to 1.209
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
12.Secondary Outcome
Title Alive and Progression-free at 12 Months (APF12), Full Analysis Set
Hide Description Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
21.4
(17.2 to 26.0)
16.8
(13.1 to 21.1)
15.3
(11.4 to 19.7)
13.Secondary Outcome
Title Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set
Hide Description Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.6
(19.7 to 31.8)
21.2
(15.9 to 27.0)
15.0
(10.2 to 20.7)
14.Secondary Outcome
Title Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set
Hide Description Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
15.2
(9.6 to 21.8)
9.7
(5.4 to 15.7)
15.6
(9.6 to 22.9)
15.Secondary Outcome
Title PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Median (95% Confidence Interval)
Unit of Measure: Months
14.6
(11.3 to 17.8)
11.9
(8.9 to 14.6)
11.5
(10.3 to 12.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0477
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.683 to 0.998
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7885
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.809 to 1.175
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
16.Secondary Outcome
Title PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Hide Description

Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Median (95% Confidence Interval)
Unit of Measure: Months
17.2
(12.1 to 24.8)
13.4
(9.7 to 17.5)
11.3
(8.9 to 14.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0053
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.549 to 0.901
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1336
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.651 to 1.059
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
17.Secondary Outcome
Title PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description

Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Median (95% Confidence Interval)
Unit of Measure: Months
10.7
(7.5 to 16.6)
9.4
(7.0 to 13.7)
11.6
(10.3 to 13.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8148
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.772 to 1.391
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2684
Comments The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.636 to 1.134
Estimation Comments The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.
18.Secondary Outcome
Title Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Number
Unit of Measure: percentage of participants
36.3 25.7 49.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.422 to 0.788
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.35
Confidence Interval (2-Sided) 95%
0.253 to 0.485
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
19.Secondary Outcome
Title Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Hide Description Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Number
Unit of Measure: percentage of participants
46.8 27.8 48.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7708
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.639 to 1.394
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.41
Confidence Interval (2-Sided) 95%
0.268 to 0.610
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
20.Secondary Outcome
Title Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Number
Unit of Measure: percentage of participants
20.4 22.6 50.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.24
Confidence Interval (2-Sided) 95%
0.135 to 0.406
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6195
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.469 to 1.566
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
21.Secondary Outcome
Title Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population
Hide Description

Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.

unconfirmed responses are excluded.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Durvalumab Cisplatin Ineligible Population include all patients who had received D monotherapy and were not eligible for cisplatin treatment at baseline (per eCRF).
Arm/Group Title Monotherapy - PD-L1 High Monotherapy - PD-L1 Low/Negative Monotherapy - Total
Hide Arm/Group Description:
MEDI4736 (Durvalumab) - PD-L1 high
MEDI4736 (Durvalumab) - PD-L1 low/negative
MEDI4736 (Durvalumab)
Overall Number of Participants Analyzed 87 56 143
Measure Type: Number
Unit of Measure: percentage of participants
23.0 17.9 21.0
22.Secondary Outcome
Title Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Number
Unit of Measure: percentage of participants
41.5 31.8 55.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.56
Confidence Interval (2-Sided) 95%
0.410 to 0.759
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
0.267 to 0.500
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
23.Secondary Outcome
Title Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Hide Description Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Number
Unit of Measure: percentage of participants
49.8 34.4 53.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4959
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.590 to 1.291
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.46
Confidence Interval (2-Sided) 95%
0.305 to 0.679
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
24.Secondary Outcome
Title Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Number
Unit of Measure: percentage of participants
29.2 27.7 59.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.27
Confidence Interval (2-Sided) 95%
0.160 to 0.448
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8074
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.623 to 1.836
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
25.Secondary Outcome
Title Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Number
Unit of Measure: percentage of participants
38.0 28.0 50.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.432 to 0.802
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
0.270 to 0.512
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
26.Secondary Outcome
Title Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Hide Description Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Number
Unit of Measure: percentage of participants
47.3 30.6 48.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7717
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.639 to 1.394
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.46
Confidence Interval (2-Sided) 95%
0.303 to 0.682
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
27.Secondary Outcome
Title Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Hide Description Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Number
Unit of Measure: percentage of participants
24.1 24.1 53.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.26
Confidence Interval (2-Sided) 95%
0.151 to 0.439
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Monotherapy
Comments monotherapy as reference.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9692
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.556 to 1.759
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.
28.Secondary Outcome
Title Duration of Response (DoR), Full Analysis Set
Hide Description Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Median (Inter-Quartile Range)
Unit of Measure: Months
11.1 [1] 
(4.3 to NA)
9.3 [1] 
(5.4 to NA)
5.7
(3.7 to 9.3)
[1]
upper limit is not reached
29.Secondary Outcome
Title Duration of Response (DoR), PD-L1-High Analysis Set
Hide Description Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Median (Inter-Quartile Range)
Unit of Measure: Months
10.0 [1] 
(3.8 to NA)
18.5 [1] 
(5.6 to NA)
5.8
(3.7 to 11.5)
[1]
upper limit is not reached.
30.Secondary Outcome
Title Duration of Response (DoR), PD-L1-Low/Negative Analysis Set
Hide Description Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Median (Inter-Quartile Range)
Unit of Measure: Months
12.9 [1] 
(5.5 to NA)
5.6 [1] 
(3.8 to NA)
5.7
(3.9 to 8.2)
[1]
upper limit is not reached.
31.Secondary Outcome
Title Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set
Hide Description Blood samples were collected to determine the serum concentration of durvalumab.
Time Frame Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab
Arm/Group Title Combination Therapy Monotherapy
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Overall Number of Participants Analyzed 339 343
Mean (Standard Deviation)
Unit of Measure: μg/mL
Week 0 - Predose Number Analyzed 329 participants 339 participants
NA [1]   (NA) NA [1]   (NA)
Week 0 - Postdose Number Analyzed 328 participants 334 participants
511  (338) 484  (162)
Week 4 - Predose Number Analyzed 285 participants 300 participants
75.3  (84.4) 78.9  (56.5)
Week 12 - Predose Number Analyzed 198 participants 195 participants
125  (97.7) 144  (82.5)
Week 12 - Postdose Number Analyzed 184 participants 186 participants
594  (298) 576  (233)
Week 24 - Predose Number Analyzed 127 participants 119 participants
150  (94.4) 163  (82.5)
Week 24 - Postdose Number Analyzed 126 participants 116 participants
604  (249) 600  (244)
Follow-up Month 3 Number Analyzed 77 participants 66 participants
23.3  (50) 19.9  (18.4)
[1]
week 0 pre-dose serum concentrations are below the level of detection
32.Secondary Outcome
Title Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set
Hide Description Blood samples were collected to determine the serum concentration of tremelimumab.
Time Frame Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab
Arm/Group Title Combination Therapy
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
Overall Number of Participants Analyzed 339
Mean (Standard Deviation)
Unit of Measure: μg/mL
Week 0 - Predose Number Analyzed 332 participants
NA [1]   (NA)
Week 0 - Postdose Number Analyzed 332 participants
24.0  (11.5)
Week 4 - Predose Number Analyzed 283 participants
3.75  (3.18)
Week 12 - Predose Number Analyzed 197 participants
5.43  (4.01)
Week 12 - Postdose Number Analyzed 182 participants
28.1  (13.2)
Follow-up Month 3 Number Analyzed 63 participants
0.943  (1.40)
[1]
week 0 pre-dose serum concentrations are below the level of detection
33.Secondary Outcome
Title Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients
Hide Description Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time Frame At week 0, 4, 12 and 24, and at follow-up Month 3.
Hide Outcome Measure Data
Hide Analysis Population Description
ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result
Arm/Group Title Combination Therapy Monotherapy
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Overall Number of Participants Analyzed 340 345
Measure Type: Count of Participants
Unit of Measure: Participants
ADA evaluable patients Number Analyzed 340 participants 345 participants
293
  86.2%
302
  87.5%
ADA positive at any visit (ADA Prevalence) Number Analyzed 293 participants 302 participants
37
  12.6%
31
  10.3%
Treatment-emergent ADA positive (ADA Incidence) Number Analyzed 293 participants 302 participants
28
   9.6%
11
   3.6%
Treatment-boosted ADA Number Analyzed 293 participants 302 participants
0
   0.0%
1
   0.3%
Treatment-induced ADA (Positive Post-baseline only) Number Analyzed 293 participants 302 participants
28
   9.6%
10
   3.3%
ADA Positive at Baseline only Number Analyzed 293 participants 302 participants
8
   2.7%
18
   6.0%
ADA Positive Post-baseline and Positive at Baseline Number Analyzed 293 participants 302 participants
1
   0.3%
3
   1.0%
Persistently Positive Number Analyzed 293 participants 302 participants
15
   5.1%
8
   2.6%
Transiently Positive Number Analyzed 293 participants 302 participants
14
   4.8%
5
   1.7%
nAb Positive at any visit Number Analyzed 293 participants 302 participants
3
   1.0%
2
   0.7%
34.Secondary Outcome
Title Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients
Hide Description Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time Frame At week 0, 4, 12 and at follow-up Month 3.
Hide Outcome Measure Data
Hide Analysis Population Description
ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result
Arm/Group Title Combination Therapy
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
Overall Number of Participants Analyzed 340
Measure Type: Count of Participants
Unit of Measure: Participants
ADA evaluable patients Number Analyzed 340 participants
292
  85.9%
ADA positive at any visit (ADA Prevalence) Number Analyzed 292 participants
64
  21.9%
Treatment-emergent ADA positive (ADA Incidence) Number Analyzed 292 participants
54
  18.5%
Treatment-boosted ADA Number Analyzed 292 participants
1
   0.3%
Treatment-induced ADA (Positive Post-baseline only) Number Analyzed 292 participants
53
  18.2%
ADA Positive at Baseline only Number Analyzed 292 participants
8
   2.7%
ADA Positive Post-baseline and Positive at Baseline Number Analyzed 292 participants
3
   1.0%
Persistently Positive Number Analyzed 292 participants
31
  10.6%
Transiently Positive Number Analyzed 292 participants
25
   8.6%
nAb Positive at any visit Number Analyzed 292 participants
50
  17.1%
35.Secondary Outcome
Title Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

Higher score represent worse outcome.
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Mean (Standard Error)
Unit of Measure: Scores on a scale
NFBLSI - 18 Score (Average overall visits) Number Analyzed 220 participants 204 participants 189 participants
-3.7  (0.70) -3.1  (0.76) -5.2  (0.82)
FACT-BL TOI (Average overall visits) Number Analyzed 220 participants 204 participants 189 participants
-5.5  (0.87) -3.9  (0.95) -7.2  (1.02)
FACT-BL Total score (Average overall visits) Number Analyzed 220 participants 204 participants 189 participants
-7.2  (1.19) -4.7  (1.30) -8.8  (1.39)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1617
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.5
Confidence Interval (2-Sided) 95%
-0.6 to 3.59
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0578
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
-0.07 to 4.29
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2003
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
-0.91 to 4.32
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0178
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.3
Confidence Interval (2-Sided) 95%
0.57 to 6.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3765
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
-1.96 to 5.17
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0300
Comments MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.1
Confidence Interval (2-Sided) 95%
0.40 to 7.81
Estimation Comments [Not Specified]
36.Secondary Outcome
Title Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

Higher score represent worse
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Mean (Standard Error)
Unit of Measure: Scores on a scale
NFBLSI - 18 Score (Average overall visits) Number Analyzed 129 participants 131 participants 119 participants
-3.9  (0.85) -2.0  (0.87) -5.7  (0.95)
FACT-BL TOI (Average overall visits) Number Analyzed 129 participants 131 participants 119 participants
-5.8  (1.09) -2.6  (1.11) -8.0  (1.22)
FACT-BL Total score (Average overall visits) Number Analyzed 129 participants 131 participants 119 participants
-8.0  (1.47) -2.7  (1.51) -10.1  (1.65)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1373
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
-0.6 to 4.36
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0034
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.8
Confidence Interval (2-Sided) 95%
1.26 to 6.27
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1774
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.2
Confidence Interval (2-Sided) 95%
-1.00 to 5.39
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 5.4
Confidence Interval (2-Sided) 95%
2.19 to 8.65
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3494
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
-2.27 to 6.38
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7.3
Confidence Interval (2-Sided) 95%
2.96 to 11.71
Estimation Comments [Not Specified]
37.Secondary Outcome
Title Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

Higher score represent worse
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Mean (Standard Error)
Unit of Measure: Scores on a scale
NFBLSI - 18 Score (Average overall visits) Number Analyzed 91 participants 73 participants 69 participants
-3.4  (1.01) -3.8  (1.18) -2.0  (1.16)
FACT-BL TOI (Average overall visits) Number Analyzed 91 participants 73 participants 69 participants
-4.9  (1.18) -5.0  (1.39) -3.0  (1.36)
FACT-BL Total score (Average overall visits) Number Analyzed 91 participants 73 participants 69 participants
-5.7  (1.62) -6.5  (1.90) -3.2  (1.86)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3865
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.3
Confidence Interval (2-Sided) 95%
-4.35 to 1.69
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments NFBLSI- 18 score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2840
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-5.05 to 1.49
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2970
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.9
Confidence Interval (2-Sided) 95%
-5.41 to 1.66
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL TOI (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3026
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.0
Confidence Interval (2-Sided) 95%
-5.85 to 1.83
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3168
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.5
Confidence Interval (2-Sided) 95%
-7.29 to 2.38
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments FACT-BL Total score (Average overall visits)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2179
Comments MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.3
Confidence Interval (2-Sided) 95%
-8.51 to 1.96
Estimation Comments [Not Specified]
38.Secondary Outcome
Title Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 342 346 344
Measure Type: Count of Participants
Unit of Measure: Participants
Patients with improvement in fatigue Number Analyzed 141 participants 129 participants 115 participants
38
  27.0%
37
  28.7%
24
  20.9%
Patient with deterioration in pain Number Analyzed 265 participants 270 participants 226 participants
142
  53.6%
130
  48.1%
83
  36.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2419
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
0.8 to 2.6
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1553
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.5
Confidence Interval (2-Sided) 95%
0.9 to 2.8
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2
Confidence Interval (2-Sided) 95%
1.4 to 2.8
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0148
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
1.1 to 2.3
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
39.Secondary Outcome
Title Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 205 209 207
Measure Type: Count of Participants
Unit of Measure: Participants
Patients with improvement in fatigue Number Analyzed 86 participants 83 participants 74 participants
23
  26.7%
24
  28.9%
14
  18.9%
Patient with deterioration in pain Number Analyzed 156 participants 164 participants 145 participants
78
  50.0%
71
  43.3%
51
  35.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2473
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
0.7 to 3.4
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0148
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
0.8 to 3.8
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0090
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
1.2 to 3.0
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1510
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
0.9 to 2.3
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
40.Secondary Outcome
Title Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Hide Description

Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Hide Outcome Measure Data
Hide Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:

<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description:
MEDI4736 (Durvalumab) + Tremelimumab
MEDI4736 (Durvalumab)
Standard of Care Chemotherapy Treatment
Overall Number of Participants Analyzed 137 137 137
Measure Type: Count of Participants
Unit of Measure: Participants
Patients with improvement in fatigue Number Analyzed 55 participants 46 participants 41 participants
15
  27.3%
13
  28.3%
10
  24.4%
Patient with deterioration in pain Number Analyzed 109 participants 106 participants 81 participants
64
  58.7%
59
  55.7%
32
  39.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6763
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.2
Confidence Interval (2-Sided) 95%
0.5 to 3.2
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patients with improvement in fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6539
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.2
Confidence Interval (2-Sided) 95%
0.5 to 3.3
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0092
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.2
Confidence Interval (2-Sided) 95%
1.2 to 4.0
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Monotherapy, Standard of Care
Comments Patient with deterioration in pain
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0324
Comments P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
1.1 to 3.5
Estimation Comments The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.
Time Frame From first administration of study treatment up to 90 days after last dose of study medication or date of initiation of the first subsequent therapy, whichever occurs first, approximately 5 years. All-cause mortality, from screening up to data cut-off date (27JAN2020, approximately 5 years).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Combination Therapy Monotherapy Standard of Care
Hide Arm/Group Description MEDI4736 (Durvalumab) + Tremelimumab MEDI4736 (Durvalumab) Standard of Care Chemotherapy Treatment
All-Cause Mortality
Combination Therapy Monotherapy Standard of Care
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   255/342 (74.56%)      263/346 (76.01%)      270/344 (78.49%)    
Hide Serious Adverse Events
Combination Therapy Monotherapy Standard of Care
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   179/340 (52.65%)      139/345 (40.29%)      125/313 (39.94%)    
Blood and lymphatic system disorders       
Anaemia † 1  2/340 (0.59%)  2 7/345 (2.03%)  9 9/313 (2.88%)  9
Bone marrow failure † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Febrile neutropenia † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 4/313 (1.28%)  4
Haematotoxicity † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 3/313 (0.96%)  4
Leukopenia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 3/313 (0.96%)  3
Neutropenia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Pancytopenia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Thrombocytopenia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 6/313 (1.92%)  6
Cardiac disorders       
Acute coronary syndrome † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Acute myocardial infarction † 1  0/340 (0.00%)  0 3/345 (0.87%)  4 0/313 (0.00%)  0
Angina pectoris † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 1/313 (0.32%)  1
Atrial fibrillation † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 2/313 (0.64%)  2
Cardiac arrest † 1  0/340 (0.00%)  0 3/345 (0.87%)  3 3/313 (0.96%)  3
Cardiac failure † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 1/313 (0.32%)  1
Cardiac failure acute † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Cardiac failure chronic † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Cardio-respiratory arrest † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Left ventricular dysfunction † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Myocardial infarction † 1  2/340 (0.59%)  2 5/345 (1.45%)  5 1/313 (0.32%)  1
Myocarditis † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 0/313 (0.00%)  0
Stress cardiomyopathy † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Supraventricular tachycardia † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Endocrine disorders       
Adrenal insufficiency † 1  3/340 (0.88%)  3 0/345 (0.00%)  0 0/313 (0.00%)  0
Hyperthyroidism † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypophysitis † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypopituitarism † 1  4/340 (1.18%)  4 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypothyroidism † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Thyroiditis † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Eye disorders       
Retinal detachment † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 0/313 (0.00%)  0
Gastrointestinal disorders       
Abdominal hernia † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Abdominal pain † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Colitis † 1  7/340 (2.06%)  7 0/345 (0.00%)  0 0/313 (0.00%)  0
Colonic fistula † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Constipation † 1  7/340 (2.06%)  8 3/345 (0.87%)  3 1/313 (0.32%)  1
Diarrhoea † 1  16/340 (4.71%)  18 2/345 (0.58%)  2 4/313 (1.28%)  4
Duodenitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Enteritis † 1  2/340 (0.59%)  3 0/345 (0.00%)  0 0/313 (0.00%)  0
Enterocolitis † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Enterovesical fistula † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Gastric ulcer † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Gastritis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Gastritis erosive † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Gastrointestinal haemorrhage † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Haemorrhoidal haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Ileus † 1  2/340 (0.59%)  3 1/345 (0.29%)  1 1/313 (0.32%)  1
Immune-mediated enterocolitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Inguinal hernia † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Intestinal obstruction † 1  3/340 (0.88%)  5 3/345 (0.87%)  3 0/313 (0.00%)  0
Large intestinal obstruction † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Large intestine perforation † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Lower gastrointestinal haemorrhage † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Melaena † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Nausea † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 3/313 (0.96%)  3
Pancreatitis † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 0/313 (0.00%)  0
Pancreatitis acute † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 1/313 (0.32%)  1
Rectal haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Small intestinal obstruction † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Stomatitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Vomiting † 1  5/340 (1.47%)  5 1/345 (0.29%)  1 4/313 (1.28%)  4
General disorders       
Asthenia † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 0/313 (0.00%)  0
Chest pain † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Death † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Extravasation † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Fatigue † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 1/313 (0.32%)  1
General physical health deterioration † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Generalised oedema † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hernia pain † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Malaise † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Mucosal inflammation † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Multiple organ dysfunction syndrome † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Non-cardiac chest pain † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Oedema peripheral † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 1/313 (0.32%)  1
Pain † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Pyrexia † 1  16/340 (4.71%)  19 6/345 (1.74%)  6 13/313 (4.15%)  13
Hepatobiliary disorders       
Acute hepatic failure † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Cholecystitis acute † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Cholecystitis chronic † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Cholestasis † 1  0/340 (0.00%)  0 1/345 (0.29%)  2 0/313 (0.00%)  0
Drug-induced liver injury † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 0/313 (0.00%)  0
Hepatic function abnormal † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hepatitis † 1  2/340 (0.59%)  2 2/345 (0.58%)  2 0/313 (0.00%)  0
Hepatitis cholestatic † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Hepatotoxicity † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Immune-mediated hepatitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Liver abscess † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Immune system disorders       
Anaphylactic shock † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Contrast media reaction † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Infections and infestations       
Abdominal abscess † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Abscess † 1  1/340 (0.29%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Amoebic dysentery † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Anal abscess † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Appendicitis † 1  1/340 (0.29%)  2 1/345 (0.29%)  1 0/313 (0.00%)  0
Bacteraemia † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 1/313 (0.32%)  1
Bronchitis † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Cellulitis † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 2/313 (0.64%)  2
Clostridium difficile infection † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Cystitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Device related infection † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Device related sepsis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Diverticulitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Encephalitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Enterococcal infection † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Escherichia sepsis † 1  2/340 (0.59%)  3 0/345 (0.00%)  0 0/313 (0.00%)  0
Escherichia urinary tract infection † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Gastroenteritis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 1/313 (0.32%)  1
Influenza † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Listeriosis † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Lower respiratory tract infection † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Nasopharyngitis † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Oral herpes † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Orchitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Osteomyelitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Otitis media chronic † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Peritonitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Pneumocystis jirovecii pneumonia † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Pneumonia † 1  15/340 (4.41%)  15 8/345 (2.32%)  9 2/313 (0.64%)  2
Pneumonia bacterial † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Pneumonia pneumococcal † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Postoperative wound infection † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Prostatic abscess † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Pseudomonas infection † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Pyelonephritis † 1  3/340 (0.88%)  3 6/345 (1.74%)  7 6/313 (1.92%)  6
Pyelonephritis acute † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 1/313 (0.32%)  1
Pyelonephritis chronic † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  3
Respiratory tract infection † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 3/313 (0.96%)  3
Scrotal abscess † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Sepsis † 1  3/340 (0.88%)  3 11/345 (3.19%)  11 4/313 (1.28%)  6
Septic shock † 1  3/340 (0.88%)  4 2/345 (0.58%)  2 1/313 (0.32%)  1
Sinusitis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Urethritis † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Urinary tract infection † 1  21/340 (6.18%)  26 17/345 (4.93%)  23 21/313 (6.71%)  28
Urinary tract infection bacterial † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Urinary tract infection pseudomonal † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Urosepsis † 1  7/340 (2.06%)  8 4/345 (1.16%)  4 2/313 (0.64%)  2
Injury, poisoning and procedural complications       
Ankle fracture † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Concussion † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Facial bones fracture † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Head injury † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Hip fracture † 1  2/340 (0.59%)  2 2/345 (0.58%)  2 1/313 (0.32%)  1
Post procedural fever † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Post procedural haemorrhage † 1  1/340 (0.29%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Post-traumatic pain † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Procedural complication † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Procedural haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Radiation pneumonitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Stoma obstruction † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Urostomy complication † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Investigations       
Alanine aminotransferase increased † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Amylase increased † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Aspartate aminotransferase increased † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Blood creatine phosphokinase increased † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Blood creatinine increased † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 2/313 (0.64%)  2
Blood sodium decreased † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Cardiac murmur † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Haemoglobin decreased † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Lipase increased † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Liver function test increased † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Neutrophil count decreased † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 4/313 (1.28%)  4
Oxygen saturation decreased † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Platelet count decreased † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 6/313 (1.92%)  8
Transaminases increased † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 1/313 (0.32%)  1
Dehydration † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 2/313 (0.64%)  2
Diabetes mellitus † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Diabetic ketoacidosis † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Glucose tolerance impaired † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Gout † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  2
Hypercalcaemia † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 1/313 (0.32%)  1
Hypercreatininaemia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Hyperglycaemia † 1  1/340 (0.29%)  1 2/345 (0.58%)  2 0/313 (0.00%)  0
Hyperkalaemia † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 0/313 (0.00%)  0
Hypernatraemia † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypoglycaemia † 1  3/340 (0.88%)  3 0/345 (0.00%)  0 1/313 (0.32%)  1
Hyponatraemia † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 1/313 (0.32%)  1
Type 2 diabetes mellitus † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthralgia † 1  0/340 (0.00%)  0 3/345 (0.87%)  3 0/313 (0.00%)  0
Arthritis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Autoimmune arthritis † 1  0/340 (0.00%)  0 1/345 (0.29%)  2 0/313 (0.00%)  0
Back pain † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 0/313 (0.00%)  0
Bone pain † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Flank pain † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Groin pain † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Musculoskeletal chest pain † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Myopathy † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Myositis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Osteoarthritis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Pain in extremity † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenocarcinoma of colon † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 1/313 (0.32%)  1
Basal cell carcinoma † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Bladder cancer † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Cholangiocarcinoma † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Colon cancer † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Hepatic cancer † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Meningioma † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Neuroendocrine carcinoma † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Oesophageal carcinoma † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Prostate cancer † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 1/313 (0.32%)  1
Renal adenoma † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Renal neoplasm † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Transitional cell carcinoma recurrent † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Nervous system disorders       
Cerebellar infarction † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Cerebral haemorrhage † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Cerebral infarction † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 1/313 (0.32%)  1
Cerebral ischaemia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Cerebral thrombosis † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Cerebrovascular accident † 1  3/340 (0.88%)  3 2/345 (0.58%)  2 2/313 (0.64%)  2
Encephalopathy † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Extrapyramidal disorder † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Facial paralysis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Immune-mediated neuropathy † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Ischaemic stroke † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Lethargy † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Loss of consciousness † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Migraine † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Myasthenia gravis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Myasthenic syndrome † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Myoclonus † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Presyncope † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Somnolence † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Syncope † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Product Issues       
Device dislocation † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 1/313 (0.32%)  1
Device occlusion † 1  1/340 (0.29%)  1 2/345 (0.58%)  2 2/313 (0.64%)  2
Psychiatric disorders       
Completed suicide † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Confusional state † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 1/313 (0.32%)  1
Delirium † 1  0/340 (0.00%)  0 2/345 (0.58%)  2 0/313 (0.00%)  0
Depression † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Psychotic disorder † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury † 1  6/340 (1.76%)  6 5/345 (1.45%)  5 8/313 (2.56%)  9
Azotaemia † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Bladder pain † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Bladder tamponade † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Chronic kidney disease † 1  1/340 (0.29%)  2 1/345 (0.29%)  1 0/313 (0.00%)  0
Cystitis noninfective † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Dysuria † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Haematuria † 1  3/340 (0.88%)  3 2/345 (0.58%)  2 4/313 (1.28%)  4
Hydronephrosis † 1  4/340 (1.18%)  4 2/345 (0.58%)  2 2/313 (0.64%)  2
Nephritis † 1  1/340 (0.29%)  1 2/345 (0.58%)  2 0/313 (0.00%)  0
Nephrolithiasis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Obstructive nephropathy † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Oliguria † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Postrenal failure † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Renal failure † 1  4/340 (1.18%)  4 3/345 (0.87%)  3 1/313 (0.32%)  1
Renal impairment † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Renal vein thrombosis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Ureteric obstruction † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Urinary bladder rupture † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Urinary tract obstruction † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 0/313 (0.00%)  0
Reproductive system and breast disorders       
Penile haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Penile pain † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Uterine haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Vaginal haemorrhage † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 1/313 (0.32%)  1
Respiratory, thoracic and mediastinal disorders       
Acute pulmonary oedema † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Acute respiratory failure † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Asthma † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Chronic obstructive pulmonary disease † 1  4/340 (1.18%)  6 0/345 (0.00%)  0 0/313 (0.00%)  0
Diaphragmatic paralysis † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Dyspnoea † 1  3/340 (0.88%)  3 5/345 (1.45%)  5 1/313 (0.32%)  1
Epistaxis † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Interstitial lung disease † 1  3/340 (0.88%)  3 0/345 (0.00%)  0 0/313 (0.00%)  0
Pleural effusion † 1  2/340 (0.59%)  2 0/345 (0.00%)  0 0/313 (0.00%)  0
Pleuritic pain † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Pneumonia aspiration † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Pneumonitis † 1  5/340 (1.47%)  5 2/345 (0.58%)  3 0/313 (0.00%)  0
Pulmonary embolism † 1  4/340 (1.18%)  4 3/345 (0.87%)  3 6/313 (1.92%)  6
Respiratory failure † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Skin and subcutaneous tissue disorders       
Drug eruption † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 1/313 (0.32%)  1
Rash † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 0/313 (0.00%)  0
Stevens-Johnson syndrome † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Vascular disorders       
Circulatory collapse † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Deep vein thrombosis † 1  3/340 (0.88%)  3 0/345 (0.00%)  0 2/313 (0.64%)  2
Embolism † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 2/313 (0.64%)  2
Extremity necrosis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypertensive emergency † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Hypertensive urgency † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Hypotension † 1  2/340 (0.59%)  2 1/345 (0.29%)  1 0/313 (0.00%)  0
Intermittent claudication † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 0/313 (0.00%)  0
Peripheral artery thrombosis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
Vasculitis † 1  1/340 (0.29%)  1 0/345 (0.00%)  0 0/313 (0.00%)  0
1
Term from vocabulary, MedDRA 22.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Combination Therapy Monotherapy Standard of Care
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   306/340 (90.00%)      312/345 (90.43%)      299/313 (95.53%)    
Blood and lymphatic system disorders       
Anaemia † 1  51/340 (15.00%)  53 58/345 (16.81%)  63 163/313 (52.08%)  222
Leukopenia † 1  1/340 (0.29%)  1 1/345 (0.29%)  1 25/313 (7.99%)  50
Neutropenia † 1  0/340 (0.00%)  0 1/345 (0.29%)  3 89/313 (28.43%)  187
Thrombocytopenia † 1  1/340 (0.29%)  1 7/345 (2.03%)  10 47/313 (15.02%)  64
Ear and labyrinth disorders       
Tinnitus † 1  3/340 (0.88%)  3 1/345 (0.29%)  1 19/313 (6.07%)  22
Endocrine disorders       
Hyperthyroidism † 1  21/340 (6.18%)  22 10/345 (2.90%)  10 1/313 (0.32%)  1
Hypothyroidism † 1  31/340 (9.12%)  34 23/345 (6.67%)  23 0/313 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain † 1  41/340 (12.06%)  47 37/345 (10.72%)  50 27/313 (8.63%)  31
Abdominal pain upper † 1  19/340 (5.59%)  24 4/345 (1.16%)  4 8/313 (2.56%)  9
Constipation † 1  79/340 (23.24%)  88 66/345 (19.13%)  73 89/313 (28.43%)  113
Diarrhoea † 1  99/340 (29.12%)  146 63/345 (18.26%)  96 55/313 (17.57%)  78
Dry mouth † 1  23/340 (6.76%)  25 17/345 (4.93%)  18 4/313 (1.28%)  4
Dyspepsia † 1  12/340 (3.53%)  12 12/345 (3.48%)  14 18/313 (5.75%)  20
Nausea † 1  58/340 (17.06%)  65 74/345 (21.45%)  88 143/313 (45.69%)  237
Vomiting † 1  56/340 (16.47%)  66 36/345 (10.43%)  46 48/313 (15.34%)  61
General disorders       
Asthenia † 1  54/340 (15.88%)  69 40/345 (11.59%)  49 68/313 (21.73%)  106
Fatigue † 1  89/340 (26.18%)  106 98/345 (28.41%)  107 101/313 (32.27%)  127
Malaise † 1  5/340 (1.47%)  5 4/345 (1.16%)  5 19/313 (6.07%)  21
Oedema peripheral † 1  30/340 (8.82%)  39 36/345 (10.43%)  41 27/313 (8.63%)  33
Pyrexia † 1  60/340 (17.65%)  80 50/345 (14.49%)  66 43/313 (13.74%)  63
Infections and infestations       
Nasopharyngitis † 1  15/340 (4.41%)  16 18/345 (5.22%)  24 11/313 (3.51%)  13
Urinary tract infection † 1  54/340 (15.88%)  69 58/345 (16.81%)  82 46/313 (14.70%)  57
Investigations       
Alanine aminotransferase increased † 1  14/340 (4.12%)  15 19/345 (5.51%)  21 21/313 (6.71%)  24
Aspartate aminotransferase increased † 1  17/340 (5.00%)  18 15/345 (4.35%)  15 16/313 (5.11%)  21
Blood alkaline phosphatase increased † 1  17/340 (5.00%)  18 20/345 (5.80%)  22 8/313 (2.56%)  10
Blood creatinine increased † 1  17/340 (5.00%)  25 27/345 (7.83%)  33 31/313 (9.90%)  37
Lipase increased † 1  23/340 (6.76%)  29 18/345 (5.22%)  33 4/313 (1.28%)  6
Neutrophil count decreased † 1  0/340 (0.00%)  0 1/345 (0.29%)  1 55/313 (17.57%)  135
Platelet count decreased † 1  3/340 (0.88%)  3 4/345 (1.16%)  4 55/313 (17.57%)  124
Weight decreased † 1  33/340 (9.71%)  34 21/345 (6.09%)  22 18/313 (5.75%)  18
White blood cell count decreased † 1  0/340 (0.00%)  0 0/345 (0.00%)  0 29/313 (9.27%)  56
Metabolism and nutrition disorders       
Decreased appetite † 1  72/340 (21.18%)  79 66/345 (19.13%)  74 80/313 (25.56%)  102
Hyperglycaemia † 1  18/340 (5.29%)  19 9/345 (2.61%)  12 10/313 (3.19%)  15
Hyperkalaemia † 1  17/340 (5.00%)  20 18/345 (5.22%)  24 18/313 (5.75%)  27
Hypomagnesaemia † 1  8/340 (2.35%)  10 2/345 (0.58%)  2 21/313 (6.71%)  25
Musculoskeletal and connective tissue disorders       
Arthralgia † 1  42/340 (12.35%)  56 36/345 (10.43%)  45 11/313 (3.51%)  14
Back pain † 1  34/340 (10.00%)  38 41/345 (11.88%)  46 31/313 (9.90%)  34
Pain in extremity † 1  18/340 (5.29%)  21 25/345 (7.25%)  28 22/313 (7.03%)  23
Nervous system disorders       
Dizziness † 1  27/340 (7.94%)  30 15/345 (4.35%)  21 25/313 (7.99%)  32
Dysgeusia † 1  8/340 (2.35%)  9 10/345 (2.90%)  10 26/313 (8.31%)  30
Headache † 1  20/340 (5.88%)  28 18/345 (5.22%)  18 16/313 (5.11%)  19
Neuropathy peripheral † 1  3/340 (0.88%)  3 5/345 (1.45%)  5 16/313 (5.11%)  17
Psychiatric disorders       
Insomnia † 1  25/340 (7.35%)  29 25/345 (7.25%)  25 14/313 (4.47%)  15
Renal and urinary disorders       
Haematuria † 1  36/340 (10.59%)  40 39/345 (11.30%)  48 14/313 (4.47%)  15
Respiratory, thoracic and mediastinal disorders       
Cough † 1  46/340 (13.53%)  55 35/345 (10.14%)  41 18/313 (5.75%)  20
Dyspnoea † 1  24/340 (7.06%)  25 30/345 (8.70%)  32 27/313 (8.63%)  30
Hiccups † 1  2/340 (0.59%)  2 2/345 (0.58%)  2 23/313 (7.35%)  33
Productive cough † 1  20/340 (5.88%)  23 5/345 (1.45%)  5 10/313 (3.19%)  10
Skin and subcutaneous tissue disorders       
Alopecia † 1  9/340 (2.65%)  9 4/345 (1.16%)  4 33/313 (10.54%)  33
Pruritus † 1  93/340 (27.35%)  134 53/345 (15.36%)  71 14/313 (4.47%)  22
Rash † 1  58/340 (17.06%)  77 30/345 (8.70%)  38 15/313 (4.79%)  18
Vascular disorders       
Hypertension † 1  19/340 (5.59%)  20 19/345 (5.51%)  20 8/313 (2.56%)  8
1
Term from vocabulary, MedDRA 22.1
†
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Science Director
Organization: AstraZeneca
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02516241    
Other Study ID Numbers: D419BC00001
2015-001633-24 ( EudraCT Number )
First Submitted: July 13, 2015
First Posted: August 5, 2015
Results First Submitted: January 25, 2021
Results First Posted: May 13, 2021
Last Update Posted: March 29, 2024