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Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN) (CASPIAN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03043872
Recruitment Status : Active, not recruiting
First Posted : February 6, 2017
Results First Posted : March 4, 2021
Last Update Posted : March 14, 2022
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 Small Cell Lung Carcinoma Extensive Disease
Interventions Drug: Durvalumab
Drug: Tremelimumab
Drug: Carboplatin
Drug: Cisplatin
Drug: Etoposide
Enrollment 978
Recruitment Details Study was conducted in 209 study centers across 23 countries. It included a global cohort (805 patients) and China cohort (188 patients). China cohort comprised 6 patients also in the global cohort and a further 182 patients randomized after end of global cohort recruitment. Results of the global and China cohorts were reported separately.
Pre-assignment Details Patients were randomized in a 1:1:1 ratio to receive treatment with durvalumab + tremelimumab + etoposide and platinum-based chemotherapy (EP), durvalumab + EP or EP alone. Enrolment was 988 but 1 patient was counted twice in error due to re-screening, thus 987 unique participants were randomized in the study overall. Patients included in both cohorts for Started, Completed and Reasons for Not Completed are not double-counted for participant flow.
Arm/Group Title All Patients: D + T + EP All Patients: D + EP All Patients: EP
Hide Arm/Group Description

During Chemotherapy:

Patients received durvalumab (D) 1500 milligrams (mg) in combination with tremelimumab (T) 75 mg intravenous (IV) infusion every 3 weeks (Q3W) for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/meters squared [m^2]) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion every 4 weeks (Q4W) from Week 12 until progressive disease (PD), unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Period Title: Overall Study
Started [1] 329 328 330
Randomized and Included in Global Cohort Analysis 268 268 269
Received Treatment in Global Cohort 266 265 266
Randomized and Included in China Cohort Analysis 65 61 62
Received Treatment in China Cohort 65 61 62
Included in Both Cohorts (Global + China) 4 1 1
Ongoing Study at Global Cohort Final Analysis Data Cut-off (DCO) 56 56 31
Ongoing Study at China Cohort Second (Final) Analysis DCO 16 11 7
Completed [2] 51 52 18
Not Completed 278 276 312
Reason Not Completed
Withdrawal by Subject             6             6             15
Lost to Follow-up             2             1             1
Death             270             269             296
[1]
Randomized in overall study
[2]
Ongoing in overall study at long-term follow-up (LTFU) analysis DCO
Arm/Group Title All Patients: D + T + EP All Patients: D + EP All Patients: EP Total
Hide Arm/Group Description

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated. Total of all reporting groups
Overall Number of Baseline Participants 329 328 330 987
Hide Baseline Analysis Population Description
Baseline analysis was based on the global full analysis set (FAS) (all patients randomized prior to the end of global recruitment) plus the China FAS (all randomized patients in the China cohort). Patients included in both cohorts are not double-counted for the baseline analysis represented by 'All Patients'.
Age, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Al Patients Number Analyzed 329 participants 328 participants 330 participants 987 participants
<50
21
   6.4%
13
   4.0%
28
   8.5%
62
   6.3%
≥50 to <65
175
  53.2%
195
  59.5%
169
  51.2%
539
  54.6%
≥65 to <75
108
  32.8%
98
  29.9%
110
  33.3%
316
  32.0%
≥75
25
   7.6%
22
   6.7%
23
   7.0%
70
   7.1%
Global Cohort Number Analyzed 268 participants 268 participants 269 participants 805 participants
<50
16
   6.0%
10
   3.7%
20
   7.4%
46
   5.7%
≥50 to <65
138
  51.5%
157
  58.6%
137
  50.9%
432
  53.7%
≥65 to <75
91
  34.0%
82
  30.6%
90
  33.5%
263
  32.7%
≥75
23
   8.6%
19
   7.1%
22
   8.2%
64
   8.0%
China Cohort Number Analyzed 65 participants 61 participants 62 participants 188 participants
<50
5
   7.7%
3
   4.9%
8
  12.9%
16
   8.5%
≥50 to <65
40
  61.5%
39
  63.9%
33
  53.2%
112
  59.6%
≥65 to <75
17
  26.2%
16
  26.2%
20
  32.3%
53
  28.2%
≥75
3
   4.6%
3
   4.9%
1
   1.6%
7
   3.7%
[1]
Measure Analysis Population Description: Baseline data is presented for all patients, as well as separately for the global and China cohorts.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
All Patients Number Analyzed 329 participants 328 participants 330 participants 987 participants
Female
74
  22.5%
86
  26.2%
95
  28.8%
255
  25.8%
Male
255
  77.5%
242
  73.8%
235
  71.2%
732
  74.2%
Global Cohort Number Analyzed 268 participants 268 participants 269 participants 805 participants
Female
66
  24.6%
78
  29.1%
85
  31.6%
229
  28.4%
Male
202
  75.4%
190
  70.9%
184
  68.4%
576
  71.6%
China Cohort Number Analyzed 65 participants 61 participants 62 participants 188 participants
Female
8
  12.3%
9
  14.8%
10
  16.1%
27
  14.4%
Male
57
  87.7%
52
  85.2%
52
  83.9%
161
  85.6%
[1]
Measure Analysis Population Description: Baseline data is presented for all patients, as well as separately for the global and China cohorts.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
All Patients Number Analyzed 329 participants 328 participants 330 participants 987 participants
Hispanic or Latino
7
   2.1%
10
   3.0%
6
   1.8%
23
   2.3%
Not Hispanic or Latino
321
  97.6%
315
  96.0%
322
  97.6%
958
  97.1%
Unknown or Not Reported
1
   0.3%
3
   0.9%
2
   0.6%
6
   0.6%
Global Cohort Number Analyzed 268 participants 268 participants 269 participants 805 participants
Hispanic or Latino
7
   2.6%
10
   3.7%
6
   2.2%
23
   2.9%
Not Hispanic or Latino
260
  97.0%
255
  95.1%
261
  97.0%
776
  96.4%
Unknown or Not Reported
1
   0.4%
3
   1.1%
2
   0.7%
6
   0.7%
China Cohort Number Analyzed 65 participants 61 participants 62 participants 188 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
65
 100.0%
61
 100.0%
62
 100.0%
188
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Analysis Population Description: Baseline data is presented for all patients, as well as separately for the global and China cohorts.
Race   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
All Patients Number Analyzed 329 participants 328 participants 330 participants 987 participants
White
215
  65.3%
229
  69.8%
221
  67.0%
665
  67.4%
Black or African American
1
   0.3%
2
   0.6%
3
   0.9%
6
   0.6%
Asian
108
  32.8%
96
  29.3%
103
  31.2%
307
  31.1%
Other
5
   1.5%
1
   0.3%
2
   0.6%
8
   0.8%
Missing
0
   0.0%
0
   0.0%
1
   0.3%
1
   0.1%
Global Cohort Number Analyzed 268 participants 268 participants 269 participants 805 participants
White
215
  80.2%
229
  85.4%
221
  82.2%
665
  82.6%
Black or African American
1
   0.4%
2
   0.7%
3
   1.1%
6
   0.7%
Asian
47
  17.5%
36
  13.4%
42
  15.6%
125
  15.5%
Other
5
   1.9%
1
   0.4%
2
   0.7%
8
   1.0%
Missing
0
   0.0%
0
   0.0%
1
   0.4%
1
   0.1%
China Cohort Number Analyzed 65 participants 61 participants 62 participants 188 participants
White
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
65
 100.0%
61
 100.0%
62
 100.0%
188
 100.0%
Other
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Missing
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Analysis Population Description: Baseline data is presented for all patients, as well as separately for the global and China cohorts.
1.Primary Outcome
Title Overall Survival (OS) in the Global Cohort; Assessed at Global Cohort Interim Analysis; D + EP Compared With EP
Hide Description OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An interim analysis of OS in the global cohort was pre-specified after approximately 318 OS events occurred each between the D + EP and EP groups (60% maturity), and between the D + T + EP and EP groups (60% maturity). At the global cohort interim analysis DCO (11 March 2019), comparison of OS in the D + EP versus (vs) EP groups had crossed the pre-specified boundary. Since these results were considered final in terms of formal statistical testing, they are presented here as a primary outcome measure. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the global cohort final analysis is presented separately in the subsequent primary outcome measure.
Time Frame From baseline until death due to any cause. Assessed until global cohort interim analysis DCO (maximum of approximately 23 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. Interim analysis for OS in the global cohort was performed for comparison of the D + EP vs EP groups only.
Arm/Group Title Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 269
Median (95% Confidence Interval)
Unit of Measure: months
13.0
(11.5 to 14.8)
10.3
(9.3 to 11.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + EP, Global Cohort: EP
Comments D + EP vs EP. The global cohort interim analysis of OS was based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary, using the actual number of events observed as a proportion of the planned total. Boundary for declaring statistical significance was 0.0178 for a 4% overall alpha. Hazard Ratio (HR) <1 favors D + EP to be associated with a longer OS than EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0047
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.591 to 0.909
Estimation Comments The HR and confidence intervals (CIs) were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
2.Primary Outcome
Title OS in the Global Cohort; Assessed at Global Cohort Final Analysis; D + EP Compared With EP and D + T + EP Compared With EP
Hide Description OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This primary outcome measure presents OS for the analysis of D + EP vs EP and D + T + EP vs EP at the time of the global cohort final analysis DCO (27 January 2020). Analysis of D + EP vs EP at the global cohort interim analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (global cohort final analysis) is presented as a secondary outcome measure.
Time Frame From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 268 269
Median (95% Confidence Interval)
Unit of Measure: months
10.4
(9.6 to 12.0)
12.9
(11.3 to 14.7)
10.5
(9.3 to 11.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + EP, Global Cohort: EP
Comments D + EP vs EP. HR <1 favors D + EP to be associated with a longer OS than EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0032
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.625 to 0.910
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + T + EP, Global Cohort: EP
Comments

D + T + EP vs EP. The alpha level applied at the global cohort final analysis was adjusted (using a generalized Haybittle-Peto method) to account for actual alpha spent at the interim analysis based on the actual final total number of events, and thus maintain control of overall Type I error. Boundary for declaring statistical significance was 0.0418 for a 5% overall alpha.

HR <1 favors D + T + EP to be associated with a longer OS than EP.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0451
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.682 to 0.995
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
3.Primary Outcome
Title OS in the China Cohort; Assessed at China Cohort First Analysis; D + EP Compared With EP
Hide Description OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + EP vs EP in the China cohort was pre-specified at approximately 60% maturity (to ensure a similar maturity to the interim analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP at the China cohort first analysis DCO (06 January 2020), and is comparable in terms of maturity with the interim analysis of OS for D + EP vs EP in the Global cohort. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the China cohort second analysis is presented separately in the subsequent primary outcome measure.
Time Frame From baseline until death due to any cause. Assessed until China cohort first analysis DCO (maximum of approximately 19 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort. China cohort first analysis for OS was performed for comparison of the D + EP vs EP groups only.
Arm/Group Title China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 61 62
Median (95% Confidence Interval)
Unit of Measure: months
14.4 [1] 
(12.3 to NA)
10.9
(8.9 to 14.0)
[1]
Upper limit of 95% CI could not be calculated as it was not reached.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection China Cohort: D + EP, China Cohort: EP
Comments D + EP vs EP. HR <1 favors D + EP to be associated with a longer OS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0664
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.414 to 1.029
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
4.Primary Outcome
Title OS in the China Cohort; Assessed at China Cohort Second Analysis; D + EP Compared With EP and D + T + EP Compared With EP
Hide Description OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + T + EP vs EP in the China cohort was pre-specified at approximately 80% maturity (to ensure a similar maturity to the final analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP and D + T + EP vs EP at the time of the China cohort second analysis DCO (02 November 2020), and is comparable in terms of maturity with the final analysis of OS for D + EP vs EP and D + T + EP vs EP in the Global cohort. Analysis of D + EP vs EP at the China cohort first analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (China cohort second analysis) is presented as a secondary outcome measure.
Time Frame From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Median (95% Confidence Interval)
Unit of Measure: months
16.1
(11.3 to 18.6)
14.4
(12.3 to 17.0)
10.9
(8.9 to 14.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection China Cohort: D + EP, China Cohort: EP
Comments D + EP vs EP. HR <1 favors D + EP to be associated with a longer OS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1455
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.504 to 1.106
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection China Cohort: D + T + EP, China Cohort: EP
Comments D + T + EP vs EP. HR <1 favors D + T + EP to be associated with a longer OS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0314
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.439 to 0.964
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
5.Secondary Outcome
Title OS in the Global Cohort; D + T + EP Compared With D + EP
Hide Description OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP in the global cohort. The alternative treatment comparisons in the global cohort were performed as primary outcome measures.
Time Frame From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 268 268
Median (95% Confidence Interval)
Unit of Measure: months
10.4
(9.6 to 12.0)
12.9
(11.3 to 14.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + T + EP, Global Cohort: D + EP
Comments D + T + EP vs D + EP. HR <1 favors D + T + EP to be associated with a longer OS than D + EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4352
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.890 to 1.309
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
6.Secondary Outcome
Title Progression-Free Survival (PFS) in the Global Cohort
Hide Description PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 millimeters (mm) for the sum from nadir. For evaluation of non-target lesions (NTLs), PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 268 269
Median (95% Confidence Interval)
Unit of Measure: months
4.9
(4.7 to 5.9)
5.1
(4.7 to 6.2)
5.4
(4.8 to 6.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + EP, Global Cohort: EP
Comments D + EP vs EP. HR <1 favors D + EP to be associated with a longer PFS than EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0157
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.665 to 0.959
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + T + EP, Global Cohort: EP
Comments D + T + EP vs EP. HR <1 favors D + T + EP to be associated with a longer PFS than EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0568
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.696 to 1.005
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + T + EP, Global Cohort: D + EP
Comments D + T + EP vs D + EP. HR <1 favors D + T + EP to be associated with a longer PFS than D + EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7540
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.857 to 1.235
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
7.Secondary Outcome
Title Objective Response Rate (ORR) in the Global Cohort
Hide Description ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR). CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size [<10 mm short axis]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. The denominator was a subset of the FAS population who had measurable disease at baseline.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 267 268 269
Measure Type: Number
Unit of Measure: percentage of patients
74.2 79.5 70.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + EP, Global Cohort: EP
Comments D + EP vs EP. An odds ratio >1 favors D + EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0177
Comments Analysis was performed using a logistic regression model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin). P-value is based on twice the change in log-likelihood resulting from addition of a treatment factor to the model.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.61
Confidence Interval (2-Sided) 95%
1.086 to 2.401
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Global Cohort: D + T + EP, Global Cohort: EP
Comments D + T + EP vs EP. An odds ratio >1 favors D + T + EP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3611
Comments Analysis was performed using a logistic regression model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin). P-value is based on twice the change in log-likelihood resulting from addition of a treatment factor to the model.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.19
Confidence Interval (2-Sided) 95%
0.817 to 1.746
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Percentage of Patients Alive and Progression Free at 6 Months (APF6) in the Global Cohort
Hide Description The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 268 269
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
43.2
(37.1 to 49.1)
45.4
(39.3 to 51.3)
45.8
(39.5 to 51.9)
9.Secondary Outcome
Title Percentage of Patients Alive and Progression Free at 12 Months (APF12) in the Global Cohort
Hide Description The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 268 269
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
16.9
(12.6 to 21.7)
17.9
(13.5 to 22.8)
5.3
(2.9 to 8.8)
10.Secondary Outcome
Title Percentage of Patients Alive at 18 Months (OS18) in the Global Cohort
Hide Description OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
Time Frame At 18 months post-randomization. Assessed at the global cohort final analysis DCO (27 January 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 268 268 269
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
30.7
(25.2 to 36.4)
32.0
(26.5 to 37.7)
24.8
(19.7 to 30.1)
11.Secondary Outcome
Title Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations in the Global Cohort
Hide Description To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time Frame Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The global PK analysis set included all patients randomized prior to the end of global recruitment who received at least 1 dose of investigational product (IP), per the protocol for whom any post-dose PK data were available. PK for durvalumab was performed for the D + T + EP and D + EP groups only.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 257 261
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms/milliliter (μg/mL)
Week 0: peak concentration Number Analyzed 239 participants 226 participants
447.3
(78.21%)
502.6
(30.52%)
Week 3: trough concentration Number Analyzed 232 participants 237 participants
91.86
(74.36%)
109.5
(64.55%)
Week 12: trough concentration Number Analyzed 173 participants 200 participants
199.2
(49.58%)
239.3
(50.68%)
12.Secondary Outcome
Title PK of Tremelimumab; Peak and Trough Serum Concentrations in the Global Cohort
Hide Description To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time Frame Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).
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Hide Analysis Population Description
The global PK analysis set included all patients randomized prior to the end of global recruitment who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for tremelimumab was performed for the D + T + EP group only.
Arm/Group Title Global Cohort: D + T + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

Overall Number of Participants Analyzed 257
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
Week 0: peak concentration Number Analyzed 236 participants
22.77
(52.15%)
Week 3: trough concentration Number Analyzed 227 participants
4.245
(81.68%)
Week 12: trough concentration Number Analyzed 148 participants
7.576
(59.25%)
13.Secondary Outcome
Title Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab in the Global Cohort
Hide Description Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
Time Frame Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the global cohort final analysis DCO (27 January 2020).
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Hide Analysis Population Description
The global ADA evaluable patients included those in the global safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for durvalumab was performed for the D + T + EP and D + EP groups only. The denominator was durvalumab ADA evaluable patients.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 191 205
Measure Type: Count of Participants
Unit of Measure: Participants
ADA positive at any visit (ADA prevalence)
6
   3.1%
11
   5.4%
Treatment-emergent ADA positive (ADA incidence)
0
   0.0%
0
   0.0%
Treatment-boosted ADA
0
   0.0%
0
   0.0%
Treatment-induced ADA (ADA positive post-baseline only)
0
   0.0%
0
   0.0%
ADA positive at baseline only
6
   3.1%
11
   5.4%
ADA positive post-baseline and positive at baseline
0
   0.0%
0
   0.0%
Persistently positive
0
   0.0%
0
   0.0%
Transiently positive
0
   0.0%
0
   0.0%
nAb positive at any visit
1
   0.5%
0
   0.0%
14.Secondary Outcome
Title Number of Patients With ADA Response to Tremelimumab in the Global Cohort
Hide Description Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
Time Frame Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the global cohort final analysis DCO (27 January 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The global ADA evaluable patients included those in the global safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for tremelimumab was performed for the D + T + EP group only. The denominator was tremelimumab ADA evaluable patients.
Arm/Group Title Global Cohort: D + T + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

Overall Number of Participants Analyzed 178
Measure Type: Count of Participants
Unit of Measure: Participants
ADA positive at any visit (ADA prevalence)
11
   6.2%
Treatment-emergent ADA positive (ADA incidence)
5
   2.8%
Treatment-boosted ADA
0
   0.0%
Treatment-induced ADA (ADA positive post-baseline only)
5
   2.8%
ADA positive at baseline only
6
   3.4%
ADA positive post-baseline and positive at baseline
0
   0.0%
Persistently positive
4
   2.2%
Transiently positive
1
   0.6%
nAb positive at any visit
2
   1.1%
15.Secondary Outcome
Title Time to Deterioration of Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) in the Global Cohort
Hide Description The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
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Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. For QLQ-C30 function scales and global health status/HRQoL, only patients with baseline scores ≥10 (and with data available) were included in the analysis. For QLQ-C30 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 262 261 260
Median (95% Confidence Interval)
Unit of Measure: months
QLQ-C30 Global Health Status / HRQoL Number Analyzed 247 participants 239 participants 232 participants
7.2
(5.8 to 8.3)
8.4
(7.3 to 11.0)
7.4
(6.5 to 9.3)
QLQ-C30 Cognitive Functioning Number Analyzed 251 participants 245 participants 242 participants
6.0
(5.0 to 7.0)
8.4
(7.3 to 10.3)
6.0
(5.2 to 7.1)
QLQ-C30 Emotional Functioning Number Analyzed 248 participants 242 participants 240 participants
7.6
(6.6 to 9.5)
11.8
(8.6 to 16.6)
7.3
(6.7 to 8.3)
QLQ-C30 Physical Functioning Number Analyzed 247 participants 244 participants 240 participants
6.0
(5.0 to 6.9)
8.4
(7.4 to 12.0)
6.5
(6.0 to 8.2)
QLQ-C30 Role Functioning Number Analyzed 236 participants 231 participants 226 participants
5.0
(4.1 to 6.5)
7.4
(5.7 to 10.2)
5.9
(4.5 to 6.7)
QLQ-C30 Social Functioning Number Analyzed 244 participants 237 participants 236 participants
6.2
(5.0 to 7.4)
7.4
(6.5 to 8.8)
6.3
(4.9 to 7.4)
QLQ-C30 Fatigue Number Analyzed 242 participants 244 participants 232 participants
4.2
(3.1 to 4.7)
5.5
(4.0 to 6.6)
4.5
(3.5 to 5.3)
QLQ-C30 Nausea / Vomiting Number Analyzed 252 participants 245 participants 244 participants
7.5
(6.1 to 8.6)
8.4
(6.6 to 10.2)
6.6
(5.6 to 7.5)
QLQ-C30 Pain Number Analyzed 243 participants 240 participants 233 participants
6.9
(6.0 to 7.7)
8.0
(6.8 to 10.4)
6.7
(6.2 to 7.8)
QLQ-C30 Appetite Loss Number Analyzed 236 participants 231 participants 224 participants
6.9
(5.6 to 8.5)
8.3
(6.8 to 11.0)
6.6
(5.5 to 7.5)
QLQ-C30 Constipation Number Analyzed 243 participants 240 participants 229 participants
8.5
(7.1 to 10.8)
11.5
(8.3 to 14.7)
7.3
(6.2 to 9.0)
QLQ-C30 Diarrhea Number Analyzed 250 participants 244 participants 244 participants
8.9
(7.5 to 10.8)
14.7
(9.4 to 21.1)
7.7
(7.1 to 9.5)
QLQ-C30 Dyspnea Number Analyzed 227 participants 225 participants 218 participants
7.2
(5.6 to 8.3)
9.0
(7.6 to 12.7)
7.5
(6.6 to 9.0)
QLQ-C30 Insomnia Number Analyzed 226 participants 226 participants 210 participants
7.1
(6.1 to 8.6)
8.6
(7.1 to 11.8)
7.3
(6.4 to 8.3)
16.Secondary Outcome
Title Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) in the Global Cohort
Hide Description The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. For QLQ-L13 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 262 261 260
Median (95% Confidence Interval)
Unit of Measure: months
QLQ-LC13 Coughing Number Analyzed 233 participants 230 participants 230 participants
7.7
(6.9 to 10.8)
9.3
(8.0 to 14.1)
7.7
(6.7 to 9.5)
QLQ-LC13 Dyspnea Number Analyzed 249 participants 241 participants 240 participants
6.3
(4.9 to 7.4)
6.5
(5.5 to 7.8)
5.5
(4.6 to 7.2)
QLQ-LC13 Hemoptysis Number Analyzed 252 participants 243 participants 245 participants
11.4
(8.9 to 18.6)
18.3 [1] 
(14.5 to NA)
10.8
(8.4 to 11.9)
QLQ-LC13 Pain in Arm or Shoulder Number Analyzed 245 participants 241 participants 238 participants
7.1
(6.3 to 8.3)
9.7
(8.1 to 15.1)
7.6
(6.6 to 9.3)
QLQ-LC13 Pain in Chest Number Analyzed 243 participants 239 participants 240 participants
8.5
(7.2 to 10.8)
11.5
(8.4 to 15.8)
7.9
(7.2 to 9.9)
QLQ-LC13 Pain in Other Parts Number Analyzed 245 participants 236 participants 231 participants
7.4
(6.5 to 8.7)
7.8
(6.6 to 9.3)
6.6
(5.1 to 7.5)
[1]
Upper limit of 95% CI could not be calculated as it was not reached.
17.Secondary Outcome
Title Change From Baseline in Primary PRO Symptoms as Assessed by EORTC QLQ in the Global Cohort; D + T + EP Compared With EP
Hide Description A mixed model repeated measures (MMRM) analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs P. Analysis of D + EP vs EP is presented in a separate outcome measure.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. For each symptom scale, only patients with data available were included in the analysis.
Arm/Group Title Global Cohort: D + T + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 262 260
Mean (Standard Error)
Unit of Measure: scores on a scale
EORTC QLQ-LC13 Cough Number Analyzed 239 participants 232 participants
-15.1  (1.74) -14.6  (1.76)
EORTC QLQ-LC13 Dyspnea Number Analyzed 239 participants 232 participants
-6.8  (1.60) -6.6  (1.62)
EORTC QLQ-LC13 Chest pain Number Analyzed 239 participants 232 participants
-7.4  (1.65) -7.0  (1.67)
EORTC QLQ-C30 Fatigue Number Analyzed 239 participants 233 participants
-6.1  (1.84) -6.3  (1.86)
EORTC QLQ-C30 Appetite loss Number Analyzed 239 participants 233 participants
-8.7  (2.02) -9.5  (2.05)
18.Secondary Outcome
Title Change From Baseline in Primary Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the Global Cohort; D + EP Compared With EP
Hide Description A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Hide Outcome Measure Data
Hide Analysis Population Description
The global FAS included all patients randomized prior to the end of global recruitment. For each symptom scale, only patients with data available were included in the analysis.
Arm/Group Title Global Cohort: D + EP Global Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 261 260
Mean (Standard Error)
Unit of Measure: scores on a scale
EORTC QLQ-LC13 Cough Number Analyzed 232 participants 232 participants
-15.0  (1.64) -15.4  (1.72)
EORTC QLQ-LC13 Dyspnea Number Analyzed 232 participants 232 participants
-7.1  (1.44) -6.5  (1.50)
EORTC QLQ-LC13 Chest pain Number Analyzed 232 participants 232 participants
-7.8  (1.59) -7.2  (1.65)
EORTC QLQ-C30 Fatigue Number Analyzed 233 participants 233 participants
-5.8  (1.62) -4.5  (1.69)
EORTC QLQ-C30 Appetite loss Number Analyzed 233 participants 233 participants
-10.1  (1.73) -7.6  (1.81)
19.Secondary Outcome
Title OS in the China Cohort; D + T + EP Compared With D + EP
Hide Description OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP at the China cohort second analysis DCO (02 November 2020). The alternative treatment comparisons were performed as primary outcome measures.
Time Frame From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 65 61
Median (95% Confidence Interval)
Unit of Measure: months
16.1
(11.3 to 18.6)
14.4
(12.3 to 17.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection China Cohort: D + T + EP, China Cohort: D + EP
Comments D + T + EP vs D + EP. HR <1 favors D + T + EP to be associated with a longer OS than D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4470
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.574 to 1.277
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
20.Secondary Outcome
Title PFS in the China Cohort
Hide Description PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 mm for the sum from nadir. For evaluation of NTLs, PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Median (95% Confidence Interval)
Unit of Measure: months
5.6
(4.8 to 6.6)
4.9
(4.7 to 5.5)
5.5
(4.9 to 6.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection China Cohort: D + EP, China Cohort: EP
Comments D + EP vs EP. HR <1 favors D + EP to be associated with a longer PFS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8934
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.661 to 1.437
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection China Cohort: D + T + EP, China Cohort: EP
Comments D + T + EP vs EP. HR <1 favors D + T + EP to be associated with a longer PFS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1035
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.487 to 1.068
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection China Cohort: D + T + EP, China Cohort: D + EP
Comments D + T + EP vs D + EP. HR <1 favors D + T + EP to be associated with a longer PFS than D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1673
Comments Analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.522 to 1.116
Estimation Comments The HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.
21.Secondary Outcome
Title ORR in the China Cohort
Hide Description ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of CR or PR. CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size [<10 mm short axis]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Measure Type: Number
Unit of Measure: percentage of patients
84.6 78.7 72.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection China Cohort: D + EP, China Cohort: EP
Comments D + EP vs EP. An odds ratio >1 favors D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4320
Comments Analysis was performed using a logistic regression model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin). P-value is based on twice the change in log-likelihood resulting from addition of a treatment factor to the model.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.39
Confidence Interval (2-Sided) 95%
0.610 to 3.244
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection China Cohort: D + T + EP, China Cohort: EP
Comments D + T + EP vs EP. An odds ratio >1 favors D + T + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0986
Comments Analysis was performed using a logistic regression model, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin). P-value is based on twice the change in log-likelihood resulting from addition of a treatment factor to the model.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.07
Confidence Interval (2-Sided) 95%
0.874 to 5.118
Estimation Comments [Not Specified]
22.Secondary Outcome
Title APF6 in the China Cohort
Hide Description The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
43.7
(31.2 to 55.5)
35.2
(23.3 to 47.4)
43.1
(29.8 to 55.7)
23.Secondary Outcome
Title APF12 in the China Cohort
Hide Description The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
21.0
(12.0 to 31.9)
12.3
(5.4 to 22.2)
6.2
(1.6 to 15.3)
24.Secondary Outcome
Title OS18 in the China Cohort
Hide Description OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
Time Frame At 18 months post-randomization. Assessed at the China cohort second analysis DCO (02 November 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
40.0
(28.1 to 51.6)
36.1
(24.3 to 48.0)
23.4
(13.6 to 34.6)
25.Secondary Outcome
Title PK of Durvalumab; Peak and Trough Serum Concentrations in the China Cohort
Hide Description To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time Frame Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The China PK analysis set included all patients in the China cohort who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for durvalumab was performed for the D + T + EP and D + EP groups only.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 64 59
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
Week 0: peak concentration Number Analyzed 64 participants 59 participants
429.4
(19.49%)
432.0
(91.79%)
Week 3: trough concentration Number Analyzed 61 participants 54 participants
81.21
(46.14%)
96.24
(64.44%)
Week 12: trough concentration Number Analyzed 46 participants 50 participants
151.0
(29.82%)
194.4
(53.34%)
26.Secondary Outcome
Title PK of Tremelimumab; Peak and Trough Serum Concentrations in the China Cohort
Hide Description To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time Frame Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The China PK analysis set included all patients in the China cohort who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for tremelimumab was performed for the D + T + EP group only.
Arm/Group Title China Cohort: D + T + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

Overall Number of Participants Analyzed 64
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
Week 0: peak concentration Number Analyzed 64 participants
24.34
(27.05%)
Week 3: trough concentration Number Analyzed 61 participants
4.530
(60.60%)
Week 12: trough concentration Number Analyzed 45 participants
9.523
(43.94%)
27.Secondary Outcome
Title Number of Patients With ADA Response to Durvalumab in the China Cohort
Hide Description Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
Time Frame Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the China cohort second analysis DCO (02 November 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The China ADA evaluable patients included those in the China safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for durvalumab was performed for the D + T + EP and D + EP groups only. The denominator was durvalumab ADA evaluable patients.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Overall Number of Participants Analyzed 53 51
Measure Type: Count of Participants
Unit of Measure: Participants
ADA positive at any visit (ADA prevalence)
0
   0.0%
0
   0.0%
Treatment-emergent ADA positive (ADA incidence)
0
   0.0%
0
   0.0%
Treatment-boosted ADA
0
   0.0%
0
   0.0%
Treatment-induced ADA (ADA positive post-baseline only)
0
   0.0%
0
   0.0%
ADA positive at baseline only
0
   0.0%
0
   0.0%
ADA positive post-baseline and positive at baseline
0
   0.0%
0
   0.0%
Persistently positive
0
   0.0%
0
   0.0%
Transiently positive
0
   0.0%
0
   0.0%
nAb positive at any visit
0
   0.0%
0
   0.0%
28.Secondary Outcome
Title Number of Patients With ADA Response to Tremelimumab in the China Cohort
Hide Description Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
Time Frame Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the China cohort second analysis DCO (02 November 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
The China ADA evaluable patients included those in the China safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for tremelimumab was performed for the D + T + EP group only. The denominator was tremelimumab ADA evaluable patients.
Arm/Group Title China Cohort: D + T + EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

Overall Number of Participants Analyzed 51
Measure Type: Count of Participants
Unit of Measure: Participants
ADA positive at any visit (ADA prevalence)
3
   5.9%
Treatment-emergent ADA positive (ADA incidence)
3
   5.9%
Treatment-boosted ADA
0
   0.0%
Treatment-induced ADA (ADA positive post-baseline only)
3
   5.9%
ADA positive at baseline only
0
   0.0%
ADA positive post-baseline and positive at baseline
0
   0.0%
Persistently positive
3
   5.9%
Transiently positive
0
   0.0%
nAb positive at any visit
0
   0.0%
29.Secondary Outcome
Title Time to Deterioration of HRQoL and PRO Symptoms, Assessed Using EORTC QLQ in the China Cohort
Hide Description The EORTC QLQ-C30 v3 was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort. For QLQ-C30 function scales and global health status/HRQoL, only patients with baseline scores ≥10 (and with data available) were included in the analysis. For QLQ-C30 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Median (95% Confidence Interval)
Unit of Measure: months
QLQ-C30 Global Health Status / HRQoL Number Analyzed 60 participants 57 participants 55 participants
14.5 [1] 
(6.8 to NA)
15.1 [1] 
(7.6 to NA)
7.8
(6.5 to 10.9)
QLQ-C30 Cognitive Functioning Number Analyzed 60 participants 58 participants 58 participants
7.6 [1] 
(4.9 to NA)
6.8 [1] 
(2.3 to NA)
6.9 [1] 
(5.7 to NA)
QLQ-C30 Emotional Functioning Number Analyzed 60 participants 58 participants 58 participants
20.4 [1] 
(6.8 to NA)
15.5 [1] 
(5.8 to NA)
10.0 [1] 
(6.9 to NA)
QLQ-C30 Physical Functioning Number Analyzed 60 participants 58 participants 58 participants
21.8 [1] 
(6.0 to NA)
9.3 [1] 
(5.8 to NA)
7.3
(5.7 to 10.9)
QLQ-C30 Role Functioning Number Analyzed 60 participants 56 participants 57 participants
6.8
(4.9 to 21.3)
6.4
(4.2 to 13.9)
6.2
(4.1 to 10.0)
QLQ-C30 Social Functioning Number Analyzed 60 participants 57 participants 56 participants
6.7
(4.3 to 14.1)
5.8
(3.9 to 13.3)
6.5
(3.3 to 8.3)
QLQ-C30 Fatigue Number Analyzed 60 participants 58 participants 58 participants
3.7
(2.3 to 6.8)
5.3
(2.9 to 9.6)
3.9
(2.2 to 5.9)
QLQ-C30 Nausea / Vomiting Number Analyzed 59 participants 58 participants 58 participants
8.4 [1] 
(4.7 to NA)
9.3
(3.9 to 15.5)
8.2
(5.7 to 10.9)
QLQ-C30 Pain Number Analyzed 60 participants 57 participants 58 participants
6.6
(4.9 to 17.3)
6.2
(5.5 to 15.1)
6.5
(4.6 to 8.6)
QLQ-C30 Appetite Loss Number Analyzed 59 participants 57 participants 57 participants
8.4 [1] 
(2.6 to NA)
5.8 [1] 
(3.3 to NA)
6.9
(5.7 to 10.0)
QLQ-C30 Constipation Number Analyzed 59 participants 58 participants 58 participants
NA [2] 
(6.8 to NA)
12.0 [1] 
(5.8 to NA)
10.9 [1] 
(8.6 to NA)
QLQ-C30 Diarrhea Number Analyzed 59 participants 58 participants 58 participants
17.3 [1] 
(9.8 to NA)
NA [1] 
(13.3 to NA)
10.1 [1] 
(8.2 to NA)
QLQ-C30 Dyspnea Number Analyzed 60 participants 57 participants 56 participants
11.6 [1] 
(6.0 to NA)
15.5 [1] 
(9.3 to NA)
7.3
(5.7 to 10.9)
QLQ-C30 Insomnia Number Analyzed 60 participants 57 participants 58 participants
7.3 [1] 
(5.2 to NA)
15.5 [1] 
(5.6 to NA)
7.8
(6.3 to 10.9)
[1]
Upper limit of 95% CI could not be calculated as it was not reached.
[2]
Median and upper limit of 95% CI could not be calculated as they were not reached.
30.Secondary Outcome
Title Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-LC13 in the China Cohort
Hide Description The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
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Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort. For QLQ-L13 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.
Arm/Group Title China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 61 62
Median (95% Confidence Interval)
Unit of Measure: months
QLQ-LC13 Coughing Number Analyzed 58 participants 56 participants 54 participants
NA [1] 
(6.8 to NA)
15.5 [2] 
(5.8 to NA)
8.6 [2] 
(6.8 to NA)
QLQ-LC13 Dyspnea Number Analyzed 60 participants 58 participants 58 participants
6.9 [2] 
(3.4 to NA)
8.1
(5.3 to 15.5)
4.7
(2.5 to 8.6)
QLQ-LC13 Hemoptysis Number Analyzed 60 participants 58 participants 58 participants
NA [1] 
(17.3 to NA)
NA [1] 
(11.2 to NA)
10.1 [2] 
(6.9 to NA)
QLQ-LC13 Pain in Arm or Shoulder Number Analyzed 60 participants 55 participants 58 participants
NA [1] 
(6.9 to NA)
15.5 [2] 
(5.6 to NA)
8.6
(6.3 to 10.9)
QLQ-LC13 Pain in Chest Number Analyzed 59 participants 55 participants 57 participants
NA [1] 
(6.8 to NA)
15.5 [2] 
(6.8 to NA)
10.0 [2] 
(6.9 to NA)
QLQ-LC13 Pain in Other Parts Number Analyzed 60 participants 58 participants 57 participants
NA [1] 
(7.0 to NA)
9.3 [2] 
(6.2 to NA)
8.6
(5.7 to 10.9)
[1]
Median and upper limit of 95% CI could not be calculated as they were not reached.
[2]
Upper limit of 95% CI could not be calculated as it was not reached.
31.Secondary Outcome
Title Change From Baseline in Primary PRO Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the China Cohort; D + T + EP Compared With EP
Hide Description A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs EP. Analysis of D + EP vs EP is presented in a separate outcome measure.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort. For each symptom scale, only patients with data available were included in the analysis.
Arm/Group Title China Cohort: D + T + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 65 62
Mean (Standard Error)
Unit of Measure: scores on a scale
EORTC QLQ-LC13 Cough Number Analyzed 60 participants 56 participants
-12.8  (2.49) -12.9  (2.50)
EORTC QLQ-LC13 Dyspnea Number Analyzed 60 participants 56 participants
-3.6  (2.21) -0.8  (2.17)
EORTC QLQ-LC13 Chest pain Number Analyzed 60 participants 56 participants
-5.1  (2.16) -5.4  (2.16)
EORTC QLQ-C30 Fatigue Number Analyzed 60 participants 56 participants
2.8  (2.10) 2.9  (2.11)
EORTC QLQ-C30 Appetite loss Number Analyzed 60 participants 56 participants
3.0  (2.36) 0.8  (2.42)
32.Secondary Outcome
Title Change From Baseline in Primary Symptoms as Assessed by EORTC QLQ in the China Cohort; D + EP Compared With EP
Hide Description A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.
Time Frame At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Hide Outcome Measure Data
Hide Analysis Population Description
The China FAS included all randomized patients in the China cohort. For each symptom scale, only patients with data available were included in the analysis.
Arm/Group Title China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description:

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
Overall Number of Participants Analyzed 61 62
Mean (Standard Error)
Unit of Measure: scores on a scale
EORTC QLQ-LC13 Cough Number Analyzed 58 participants 56 participants
-14.9  (2.66) -16.7  (2.68)
EORTC QLQ-LC13 Dyspnea Number Analyzed 58 participants 56 participants
-2.2  (1.93) -3.0  (1.97)
EORTC QLQ-LC13 Chest pain Number Analyzed 58 participants 56 participants
-6.7  (1.93) -7.7  (1.95)
EORTC QLQ-C30 Fatigue Number Analyzed 58 participants 56 participants
1.5  (2.06) 0.8  (2.11)
EORTC QLQ-C30 Appetite loss Number Analyzed 58 participants 56 participants
3.6  (2.47) -2.2  (2.51)
Time Frame All treatment-emergent adverse events (TEAEs) were collected up to the final analysis DCO for each cohort; maximum of approximately 33 months for the Global cohort and maximum of approximately 29 months for the China cohort. Serious AEs and Deaths were collected through LTFU analysis in patients still receiving durvalumab (or within 90 days of discontinuing treatment); up to approximately 4 years.
Adverse Event Reporting Description TEAEs included those from first administration of study treatment up to and including 90 days after last dose of study treatment or up to date of initiation of the first subsequent anticancer therapy (whichever occurred first). Data from the global cohort and China cohort safety analysis sets was summarised separately. 6 patients in the China cohort were also included in the global cohort.
 
Arm/Group Title Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Hide Arm/Group Description

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

For chemotherapy (EP), patients received etoposide (80-100 mg/m^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.
All-Cause Mortality
Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   225/266 (84.59%)      218/265 (82.26%)      247/266 (92.86%)      50/65 (76.92%)      51/61 (83.61%)      55/62 (88.71%)    
Hide Serious Adverse Events
Global Cohort: D + T + EP Global Cohort: D + EP Global Cohort: EP China Cohort: D + T + EP China Cohort: D + EP China Cohort: EP
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   126/266 (47.37%)      86/265 (32.45%)      97/266 (36.47%)      31/65 (47.69%)      26/61 (42.62%)      22/62 (35.48%)    
Blood and lymphatic system disorders             
Anaemia  1  9/266 (3.38%)  11 5/265 (1.89%)  8 12/266 (4.51%)  14 2/65 (3.08%)  2 0/61 (0.00%)  0 2/62 (3.23%)  2
Bone marrow failure  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 5/65 (7.69%)  5 6/61 (9.84%)  6 7/62 (11.29%)  11
Febrile neutropenia  1  11/266 (4.14%)  12 12/265 (4.53%)  15 12/266 (4.51%)  13 2/65 (3.08%)  3 0/61 (0.00%)  0 0/62 (0.00%)  0
Granulocytopenia  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Haematotoxicity  1  1/266 (0.38%)  1 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Leukopenia  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 2/62 (3.23%)  2
Neutropenia  1  5/266 (1.88%)  5 2/265 (0.75%)  2 7/266 (2.63%)  12 0/65 (0.00%)  0 1/61 (1.64%)  1 3/62 (4.84%)  3
Pancytopenia  1  2/266 (0.75%)  3 4/265 (1.51%)  4 3/266 (1.13%)  3 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Thrombocytopenia  1  6/266 (2.26%)  6 1/265 (0.38%)  1 9/266 (3.38%)  11 3/65 (4.62%)  3 0/61 (0.00%)  0 1/62 (1.61%)  1
Cardiac disorders             
Acute myocardial infarction  1  0/266 (0.00%)  0 0/265 (0.00%)  0 2/266 (0.75%)  2 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Angina unstable  1  0/266 (0.00%)  0 2/265 (0.75%)  2 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Atrial fibrillation  1  3/266 (1.13%)  3 2/265 (0.75%)  2 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Cardiac arrest  1  1/266 (0.38%)  1 1/265 (0.38%)  1 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cardiac dysfunction  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cardiac failure  1  2/266 (0.75%)  2 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 2/61 (3.28%)  2 0/62 (0.00%)  0
Cardiac failure acute  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cardiac failure chronic  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cardiopulmonary failure  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Left ventricular failure  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Myocardial infarction  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Myocardial ischaemia  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 1/62 (1.61%)  1
Myocarditis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Pericardial effusion  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Endocrine disorders             
Adrenal insufficiency  1  2/266 (0.75%)  2 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Hyperthyroidism  1  2/266 (0.75%)  2 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hypoparathyroidism  1  2/266 (0.75%)  2 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hypopituitarism  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hypothyroidism  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Inappropriate antidiuretic hormone secretion  1  5/266 (1.88%)  5 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Secondary adrenocortical insufficiency  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Eye disorders             
Angle closure glaucoma  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Retinal detachment  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Retinopathy  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Vitreous detachment  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Gastrointestinal disorders             
Abdominal discomfort  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Abdominal pain  1  1/266 (0.38%)  1 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Acute abdomen  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Constipation  1  0/266 (0.00%)  0 2/265 (0.75%)  2 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Enteritis  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  2 1/61 (1.64%)  1 0/62 (0.00%)  0
Enterocolitis  1  4/266 (1.50%)  4 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Food poisoning  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Gastritis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Gastrooesophageal reflux disease  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Haematemesis  1  0/266 (0.00%)  0 1/265 (0.38%)  1 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Ileus  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Large intestinal haemorrhage  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Large intestinal obstruction  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Lower gastrointestinal haemorrhage  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Nausea  1  1/266 (0.38%)  1 0/265 (0.00%)  0 2/266 (0.75%)  2 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Oesophageal obstruction  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Stomatitis  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Vomiting  1  3/266 (1.13%)  3 0/265 (0.00%)  0 3/266 (1.13%)  3 0/65 (0.00%)  0 1/61 (1.64%)  1 1/62 (1.61%)  1
Colitis  1  5/266 (1.88%)  6 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Diarrhoea  1  7/266 (2.63%)  7 2/265 (0.75%)  2 4/266 (1.50%)  4 2/65 (3.08%)  2 0/61 (0.00%)  0 0/62 (0.00%)  0
Gastrointestinal haemorrhage  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Pancreatitis acute  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
General disorders             
Asthenia  1  1/266 (0.38%)  1 1/265 (0.38%)  2 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 2/62 (3.23%)  2
Chest pain  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Condition aggravated  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Death  1  4/266 (1.50%)  4 0/265 (0.00%)  0 2/266 (0.75%)  2 1/65 (1.54%)  1 2/61 (3.28%)  2 2/62 (3.23%)  2
Drowning  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Malaise  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 1/62 (1.61%)  1
Mucosal inflammation  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Multiple organ dysfunction syndrome  1  1/266 (0.38%)  1 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
General physical health deterioration  1  1/266 (0.38%)  1 2/265 (0.75%)  2 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Oedema peripheral  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Pain  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Pyrexia  1  0/266 (0.00%)  0 0/265 (0.00%)  0 2/266 (0.75%)  2 0/65 (0.00%)  0 2/61 (3.28%)  2 0/62 (0.00%)  0
Sudden cardiac death  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Sudden death  1  2/266 (0.75%)  2 2/265 (0.75%)  2 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hepatobiliary disorders             
Cholangitis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cholecystitis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cholecystitis acute  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Drug-induced liver injury  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Hepatic failure  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hepatic function abnormal  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Hepatitis  1  3/266 (1.13%)  3 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hepatotoxicity  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hyperbilirubinaemia  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Immune-mediated hepatitis  1  2/266 (0.75%)  3 0/265 (0.00%)  0 0/266 (0.00%)  0 1/65 (1.54%)  1 0/61 (0.00%)  0 0/62 (0.00%)  0
Immune system disorders             
Anaphylactic reaction  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Contrast media allergy  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Drug hypersensitivity  1  0/266 (0.00%)  0 1/265 (0.38%)  1 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Hypersensitivity  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 1/61 (1.64%)  1 0/62 (0.00%)  0
Infections and infestations             
Abdominal sepsis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Anal abscess  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Bacterial prostatitis  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Bronchitis  1  1/266 (0.38%)  1 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Clostridium difficile colitis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Cystitis  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Device related sepsis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Diverticulitis  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Gastroenteritis  1  0/266 (0.00%)  0 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 1/62 (1.61%)  1
Hepatitis C  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Herpes zoster  1  0/266 (0.00%)  0 2/265 (0.75%)  2 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Infection  1  1/266 (0.38%)  1 1/265 (0.38%)  1 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Infectious pleural effusion  1  1/266 (0.38%)  1 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Influenza  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Kidney infection  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Lower respiratory tract infection  1  3/266 (1.13%)  4 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 1/62 (1.61%)  1
Lung abscess  1  0/266 (0.00%)  0 1/265 (0.38%)  1 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Pneumocystis jirovecii pneumonia  1  2/266 (0.75%)  2 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Pneumonia  1  16/266 (6.02%)  17 6/265 (2.26%)  6 11/266 (4.14%)  12 9/65 (13.85%)  9 5/61 (8.20%)  5 2/62 (3.23%)  2
Pneumonia bacterial  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Pyelonephritis acute  1  1/266 (0.38%)  1 0/265 (0.00%)  0 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Respiratory tract infection  1  0/266 (0.00%)  0 2/265 (0.75%)  2 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Sepsis  1  0/266 (0.00%)  0 3/265 (1.13%)  3 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Septic shock  1  0/266 (0.00%)  0 3/265 (1.13%)  3 0/266 (0.00%)  0 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Systemic candida  1  0/266 (0.00%)  0 0/265 (0.00%)  0 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Upper respiratory tract infection  1  1/266 (0.38%)  1 2/265 (0.75%)  2 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0
Urinary tract infection  1  1/266 (0.38%)  1 1/265 (0.38%)  1 1/266 (0.38%)  1 0/65 (0.00%)  0 0/61 (0.00%)  0 0/62 (0.00%)  0