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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02516241
• Collaborator: (none)
• Enrollment: 1,126
• Locations: 222
• Arms: 3
• Anticipated Duration (Months): 100.9
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer

Condition or Disease	Intervention/Treatment	Phase
Urothelial Cancer	Drug: MEDI4736 (Durvalumab); Drug: Tremelimumab; Drug: Cisplatin; Drug: Carboplatin; Drug: Gemcitabine	Phase 3

Detailed Description

This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736 (Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines. The patients enrolled in the study will be randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility). Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer
• Actual Study Start Date: Nov 2, 2015
• Actual Primary Completion Date: Jan 27, 2020
• Anticipated Study Completion Date: Mar 29, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Therapy MEDI4736 (Durvalumab) + Tremelimumab	Drug: MEDI4736 (Durvalumab); IV infusion; Drug: Tremelimumab; IV infusion
Experimental: Monotherapy MEDI4736 (Durvalumab)	Drug: MEDI4736 (Durvalumab); IV infusion
Active Comparator: Standard of Care Standard of Care Chemotherapy Treatment	Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Gemcitabine; IV infusion

Outcome Measures

Primary Outcome Measures

1. To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set [From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

2. To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set [From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Secondary Outcome Measures

1. OS, Full Analysis Set - Durvalumab Monotherapy vs SoC [From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

2. OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC [From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

3. OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

4. Alive at 24 Months (OS24), Full Analysis Set [From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).]

   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

5. Alive at 24 Months (OS24), PD-L1-High Analysis Set [From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).]

   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

6. Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set [From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).]

   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

7. PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

8. PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

9. PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

10. Alive and Progression-free at 12 Months (APF12), Full Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).]

    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.

11. Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).]

    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.

12. Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).]

    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.

13. PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

14. PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

15. PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

16. Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

17. Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

18. Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

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

19. Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).]

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

20. Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).]

    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.

21. Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).]

    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.

22. Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).]

    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.

23. Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020)]

    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.

24. Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).]

    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.

25. Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).]

    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.

26. Duration of Response (DoR), Full Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).

27. Duration of Response (DoR), PD-L1-High Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).

28. Duration of Response (DoR), PD-L1-Low/Negative Analysis Set [Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).

29. Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set [Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.]

    Blood samples were collected to determine the serum concentration of durvalumab.

30. Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set [Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.]

    Blood samples were collected to determine the serum concentration of tremelimumab.

31. Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients [At week 0, 4, 12 and 24, and at follow-up Month 3.]

    Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.

32. Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients [At week 0, 4, 12 and at follow-up Month 3.]

    Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.

33. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse outcome.

34. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse

35. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse

36. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

37. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

38. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy.

• Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria: • Creatinine clearance (calculated or measured) <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection for determination • Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III heart failure.

• Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.

Exclusion Criteria:

• Prior exposure to immune-mediated therapy, including but not limited to, other anti cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.

• History of allogenic organ transplantation that requires use of immunosuppressive agents.

• Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any chronic skin condition that does not require systemic therapy • Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca • Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca.

• Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status.

• Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).

• Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).

• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90095
2	Research Site	Stanford	California	United States	94305
3	Research Site	Aurora	Colorado	United States	80045
4	Research Site	New Haven	Connecticut	United States	06520
5	Research Site	Tampa	Florida	United States	33612
6	Research Site	Atlanta	Georgia	United States	30322
7	Research Site	Louisville	Kentucky	United States	40202
8	Research Site	Boston	Massachusetts	United States	02215
9	Research Site	Ann Arbor	Michigan	United States	48109
10	Research Site	Detroit	Michigan	United States	48201
11	Research Site	Omaha	Nebraska	United States	68130
12	Research Site	New York	New York	United States	10021
13	Research Site	New York	New York	United States	10029
14	Research Site	Memphis	Tennessee	United States	38120
15	Research Site	Nashville	Tennessee	United States	37203
16	Research Site	Seattle	Washington	United States	98101
17	Research Site	Box Hill		Australia	3128
18	Research Site	Elizabeth Vale		Australia	5112
19	Research Site	Macquarie University		Australia	2109
20	Research Site	St Leonards		Australia	2065
21	Research Site	Waratah		Australia	2298
22	Research Site	Linz		Austria	4010
23	Research Site	Wien		Austria	1090
24	Research Site	Wien		Austria	1140
25	Research Site	Brussels		Belgium	1000
26	Research Site	Bruxelles		Belgium	1200
27	Research Site	Leuven		Belgium	3000
28	Research Site	Liège		Belgium	4000
29	Research Site	Barretos		Brazil	14784-400
30	Research Site	Belo Horizonte		Brazil	30380-472
31	Research Site	Ijui		Brazil	98700-000
32	Research Site	Itajai		Brazil	88310-110
33	Research Site	Porto Alegre		Brazil	90035-003
34	Research Site	Porto Alegre		Brazil	90610-000
35	Research Site	Porto Alegre		Brazil	91350-200
36	Research Site	Rio de Janeiro		Brazil	20231-050
37	Research Site	Rio de Janeiro		Brazil	22793-080
38	Research Site	Sao Paulo		Brazil	01209-000
39	Research Site	Sao Paulo		Brazil	01321-001
40	Research Site	Sao Paulo		Brazil	01509-900
41	Research Site	São José do Rio Preto		Brazil	15090-000
42	Research Site	Calgary	Alberta	Canada	T2N 4N2
43	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
44	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
45	Research Site	Vancouver	British Columbia	Canada	V5Z 4E6
46	Research Site	Halifax	Nova Scotia	Canada	B3H 1V7
47	Research Site	Hamilton	Ontario	Canada	L8V 5C2
48	Research Site	Newmarket	Ontario	Canada	L3Y 2P9
49	Research Site	Oshawa	Ontario	Canada	L1G 2B9
50	Research Site	Ottawa	Ontario	Canada	K1H 1C4
51	Research Site	Toronto	Ontario	Canada	M4N 3M5
52	Research Site	Toronto	Ontario	Canada	M5G 2M9
53	Research Site	Sherbrooke	Quebec	Canada	J1H 5N4
54	Research Site	Quebec		Canada	G1R 3S1
55	Research Site	Beijing		China	100034
56	Research Site	Beijing		China	100039
57	Research Site	Beijing		China	100191
58	Research Site	Changchun		China	130012
59	Research Site	Changsha		China	410013
60	Research Site	Chongqing		China	400038
61	Research Site	Hangzhou		China	310009
62	Research Site	Hangzhou		China	310014
63	Research Site	Nanjing		China	210008
64	Research Site	Shanghai		China	200000
65	Research Site	Shanghai		China	200032
66	Research Site	Shanghai		China	200072
67	Research Site	Shanghai		China	200080
68	Research Site	Shanghai		China	200127
69	Research Site	Shenyang		China	110001
70	Research Site	Tianjin		China	300211
71	Research Site	Xi'an		China	710061
72	Research Site	Xiamen		China	361003
73	Research Site	Herlev		Denmark	2730
74	Research Site	København Ø		Denmark	2100
75	Research Site	Odense C		Denmark	5000
76	Research Site	Århus C		Denmark	8000
77	Research Site	Bordeaux		France	33000
78	Research Site	Bordeaux		France	33076
79	Research Site	Caen Cedex		France	14076
80	Research Site	Lyon Cedex 08		France	69008
81	Research Site	Marseille cedex 09		France	13273
82	Research Site	Paris Cedex 10		France	75475
83	Research Site	Poitiers Cedex		France	86021
84	Research Site	Suresnes Cedex		France	92151
85	Research Site	Toulouse		France	31059
86	Research Site	Villejuif		France	94805
87	Research Site	Düsseldorf		Germany	40225
88	Research Site	Erlangen		Germany	91054
89	Research Site	Hannover		Germany	30625
90	Research Site	Heidelberg		Germany	69120
91	Research Site	Jena		Germany	07747
92	Research Site	München		Germany	81675
93	Research Site	Münster		Germany	48149
94	Research Site	Athens		Greece	11528
95	Research Site	Heraklion		Greece	711 11
96	Research Site	Holargos, Athens		Greece	155 62
97	Research Site	Kaliftaki, N.Kifissia, Athens		Greece	14564
98	Research Site	Maroussi, Athens		Greece	15125
99	Research Site	Patras		Greece	26500
100	Research Site	Thessaloniki		Greece	56 429
101	Research Site	Haifa		Israel	31096
102	Research Site	Jerusalem		Israel	91120
103	Research Site	Petach-Tikva		Israel	4941492
104	Research Site	Ramat Gan		Israel	5265601
105	Research Site	Zerifin		Israel	70300
106	Research Site	Arezzo		Italy	52100
107	Research Site	Meldola		Italy	47014
108	Research Site	Milano		Italy	20132
109	Research Site	Milano		Italy	20133
110	Research Site	Napoli		Italy	80131
111	Research Site	Orbassano		Italy	10043
112	Research Site	Pavia		Italy	27100
113	Research Site	Roma		Italy	00152
114	Research Site	San Giovanni Rotondo		Italy	71013
115	Research Site	Akita-shi		Japan	010-8543
116	Research Site	Bunkyo-ku		Japan	113-8603
117	Research Site	Fukuoka-shi		Japan	811-1347
118	Research Site	Hakata-shi		Japan	812-0033
119	Research Site	Hirosaki-shi		Japan	036-8563
120	Research Site	Hiroshima-shi		Japan	730-8518
121	Research Site	Izumo-shi		Japan	693-8501
122	Research Site	Kagoshima-shi		Japan	890-8520
123	Research Site	Kanazawa-shi		Japan	920-8641
124	Research Site	Kita-gun		Japan	761-0793
125	Research Site	Kobe-shi		Japan	650-0047
126	Research Site	Koshigaya-shi		Japan	343-8555
127	Research Site	Koto-ku		Japan	135-8550
128	Research Site	Kumamoto-shi		Japan	860-0008
129	Research Site	Kyoto-shi		Japan	606-8507
130	Research Site	Matsuyama-shi		Japan	791-0280
131	Research Site	Morioka-shi		Japan	028-3695
132	Research Site	Nagasaki-shi		Japan	852-8501
133	Research Site	Nagoya-shi		Japan	460-0001
134	Research Site	Nagoya-shi		Japan	466-8560
135	Research Site	Osaka-shi		Japan	541-8567
136	Research Site	Osaka-shi		Japan	545-8586
137	Research Site	Osakasayama-shi		Japan	589-8511
138	Research Site	Saga-shi		Japan	840-8571
139	Research Site	Sagamihara-shi		Japan	252-0315
140	Research Site	Sakura-shi		Japan	285-8741
141	Research Site	Sapporo-shi		Japan	060-8648
142	Research Site	Suita-shi		Japan	565-0871
143	Research Site	Takatsuki-shi		Japan	569-8686
144	Research Site	Yokohama-shi		Japan	232-0024
145	Research Site	Yokohama-shi		Japan	236-0004
146	Research Site	Incheon		Korea, Republic of	21565
147	Research Site	Seongnam-si		Korea, Republic of	13620
148	Research Site	Seoul		Korea, Republic of	02841
149	Research Site	Seoul		Korea, Republic of	03080
150	Research Site	Seoul		Korea, Republic of	03722
151	Research Site	Seoul		Korea, Republic of	05505
152	Research Site	Seoul		Korea, Republic of	135-710
153	Research Site	Guadalajara		Mexico	44280
154	Research Site	León		Mexico	37000
155	Research Site	Mexico, D.F		Mexico	01120
156	Research Site	Mexico		Mexico	06760
157	Research Site	Monterrey		Mexico	64460
158	Research Site	México		Mexico	04739
159	Research Site	Amsterdam		Netherlands	1066 CX
160	Research Site	Amsterdam		Netherlands	1081 HV
161	Research Site	Breda		Netherlands	4819 EV
162	Research Site	Enschede		Netherlands	7512 KZ
163	Research Site	Groningen		Netherlands	9713 GZ
164	Research Site	Leiden		Netherlands	2333 ZA
165	Research Site	Maastricht		Netherlands	6229 HX
166	Research Site	Nijmegen		Netherlands	6525 GA
167	Research Site	Gdańsk		Poland	80-214
168	Research Site	Gdańsk		Poland	80-462
169	Research Site	Gdynia		Poland	81-519
170	Research Site	Gliwice		Poland	44-101
171	Research Site	Olsztyn		Poland	10-228
172	Research Site	Otwock		Poland	05-400
173	Research Site	Szczecin		Poland	70-111
174	Research Site	Warszawa		Poland	02-781
175	Research Site	Lisboa		Portugal	1649-035
176	Research Site	Loures		Portugal	2674-514
177	Research Site	Porto		Portugal	4099-001
178	Research Site	Moscow		Russian Federation	105229
179	Research Site	Moscow		Russian Federation	115478
180	Research Site	Murmansk		Russian Federation	183047
181	Research Site	Nizhnyi Novgorod		Russian Federation	603001
182	Research Site	Obninsk		Russian Federation	249036
183	Research Site	Omsk		Russian Federation	644013
184	Research Site	Saint Petersburg		Russian Federation	191015
185	Research Site	Saint-Petersburg		Russian Federation	197758
186	Research Site	St. Petersburg		Russian Federation	194354
187	Research Site	St. Petersburg		Russian Federation	199178
188	Research Site	St.Petersburg		Russian Federation	191014
189	Research Site	Ufa		Russian Federation	450054
190	Research Site	Yaroslavl		Russian Federation	150054
191	Research Site	Badajoz		Spain	06008
192	Research Site	Badalona		Spain	08916
193	Research Site	Barcelona		Spain	08003
194	Research Site	Barcelona		Spain	08243
195	Research Site	Elche(Alicante)		Spain	03202
196	Research Site	Madrid		Spain	08035
197	Research Site	Madrid		Spain	28007
198	Research Site	Madrid		Spain	28040
199	Research Site	Madrid		Spain	28041
200	Research Site	Madrid		Spain	28050
201	Research Site	Pozuelo de Alarcon		Spain	28223
202	Research Site	Santiago de Compostela		Spain	15706
203	Research Site	Sevilla		Spain	41013
204	Research Site	Kaohsiung		Taiwan
205	Research Site	Taichung		Taiwan	00407
206	Research Site	Tainan		Taiwan	704
207	Research Site	Taipei		Taiwan	10002
208	Research Site	Taipei		Taiwan	112
209	Research Site	Taoyuan City		Taiwan	333
210	Research Site	Ankara		Turkey	06230
211	Research Site	Edirne		Turkey	22030
212	Research Site	Izmir		Turkey	35100
213	Research Site	Cambridge		United Kingdom	CB2 0QQ
214	Research Site	Cardiff.		United Kingdom	CF14 2TL
215	Research Site	Glasgow		United Kingdom	G12 0YN
216	Research Site	Leeds		United Kingdom	LS9 7TF
217	Research Site	London		United Kingdom	E1 1BB
218	Research Site	London		United Kingdom	SE1 9RT
219	Research Site	Manchester		United Kingdom	M20 4BX
220	Research Site	Sheffield		United Kingdom	S10 2SJ
221	Research Site	Southampton		United Kingdom	SO16 6YD
222	Research Site	Wirral		United Kingdom	CH63 4JY

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 3, 2019
• Statistical Analysis Plan - Dec 4, 2019

More Information

Additional Information:

• Redacted SAP
• Redacted Protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02516241
• Other Study ID Numbers: D419BC00001
• First Posted: Aug 5, 2015
• Last Update Posted: Jul 15, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: Urothelial Cancer; Phase III
• Additional relevant MeSH terms: Gemcitabine; Carboplatin; Durvalumab; Tremelimumab

Study Results

Participant Flow

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Period Title: Overall Study
STARTED	342	346	344
Received Treatment	340	345	313
COMPLETED	0	0	0
NOT COMPLETED	342	346	344

Baseline Characteristics

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care	Total
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment	Total of all reporting groups
Overall Participants	342	346	344	1032
Age (years) [Mean (Standard Deviation) ]
Age (years)	66.4 (9.60)	66.3 (9.9)	67.0 (9.32)	66.5 (9.60)
Age, Customized (Count of Participants)
<50	19 5.6%	22 6.4%	14 4.1%	55 5.3%
>= 50 - < 65	118 34.5%	115 33.2%	119 34.6%	352 34.1%
>= 65 - < 75	132 38.6%	141 40.8%	137 39.8%	410 39.7%
>= 75	73 21.3%	68 19.7%	74 21.5%	215 20.8%
Sex: Female, Male (Count of Participants)
Female	86 25.1%	97 28%	70 20.3%	253 24.5%
Male	256 74.9%	249 72%	274 79.7%	779 75.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 4.4%	14 4%	17 4.9%	46 4.5%
Not Hispanic or Latino	320 93.6%	329 95.1%	322 93.6%	971 94.1%
Unknown or Not Reported	7 2%	3 0.9%	5 1.5%	15 1.5%
Race/Ethnicity, Customized (Count of Participants)
White	253 74%	278 80.3%	260 75.6%	791 76.6%
Black or African American	3 0.9%	3 0.9%	0 0%	6 0.6%
Asian	72 21.1%	60 17.3%	76 22.1%	208 20.2%
Native Hawaiian or other Pacific islander	0 0%	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Other	13 3.8%	4 1.2%	8 2.3%	25 2.4%
Unknown or Not Reported	1 0.3%	1 0.3%	0 0%	2 0.2%

Outcome Measures

1. Primary Outcome

Title	To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set
Description	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	Standard of Care Chemotherapy Treatment
Measure Participants	342	344
Median (95% Confidence Interval) [Months]	15.1	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0751
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 98.66%; 0.688 to 1.063
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

2. Primary Outcome

Title	To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set
Description	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	209	207
Median (95% Confidence Interval) [Months]	14.4	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3039
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 96.99%; 0.695 to 1.139
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

3. Secondary Outcome

Title	OS, Full Analysis Set - Durvalumab Monotherapy vs SoC
Description	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	346	344
Median (95% Confidence Interval) [Months]	13.2	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8637
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.830 to 1.169
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

4. Secondary Outcome

Title	OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC
Description	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	Standard of Care Chemotherapy Treatment
Measure Participants	205	207
Median (95% Confidence Interval) [Months]	17.9	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0091
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.589 to 0.928
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

5. Secondary Outcome

Title	OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time Frame	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Median (95% Confidence Interval) [Months]	11.8	10.9	12.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7599
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.799 to 1.359
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4424
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.692 to 1.175
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

6. Secondary Outcome

Title	Alive at 24 Months (OS24), Full Analysis Set
Description	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Number (95% Confidence Interval) [percentage of participants]	39.0 11.4%	31.5 9.1%	29.0 8.4%

7. Secondary Outcome

Title	Alive at 24 Months (OS24), PD-L1-High Analysis Set
Description	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Number (95% Confidence Interval) [percentage of participants]	43.7 12.8%	36.0 10.4%	29.3 8.5%

8. Secondary Outcome

Title	Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set
Description	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time Frame	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Number (95% Confidence Interval) [percentage of participants]	32.1 9.4%	24.5 7.1%	28.6 8.3%

9. Secondary Outcome

Title	PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Median (95% Confidence Interval) [Months]	3.7	2.3	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2579
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.931 to 1.304
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 1.124 to 1.567
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

10. Secondary Outcome

Title	PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Description	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Median (95% Confidence Interval) [Months]	4.1	2.4	5.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2395
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.705 to 1.091
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2431
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.917 to 1.406
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

11. Secondary Outcome

Title	PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Median (95% Confidence Interval) [Months]	2.0	2.0	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 1.177 to 1.990
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6236
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.729 to 1.209
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

12. Secondary Outcome

Title	Alive and Progression-free at 12 Months (APF12), Full Analysis Set
Description	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Number (95% Confidence Interval) [percentage of participants]	21.4 6.3%	16.8 4.9%	15.3 4.4%

13. Secondary Outcome

Title	Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set
Description	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Number (95% Confidence Interval) [percentage of participants]	25.6 7.5%	21.2 6.1%	15.0 4.4%

14. Secondary Outcome

Title	Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set
Description	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Number (95% Confidence Interval) [percentage of participants]	15.2 4.4%	9.7 2.8%	15.6 4.5%

15. Secondary Outcome

Title	PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Median (95% Confidence Interval) [Months]	14.6	11.9	11.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0477
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.683 to 0.998
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7885
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.809 to 1.175
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

16. Secondary Outcome

Title	PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Description	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Median (95% Confidence Interval) [Months]	17.2	13.4	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.549 to 0.901
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1336
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.651 to 1.059
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

17. Secondary Outcome

Title	PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Median (95% Confidence Interval) [Months]	10.7	9.4	11.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8148
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.772 to 1.391
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2684
	Comments	The 2-sided p-value was calculated using a stratified log-rank test adjusting for visceral metastases and cisplatin eligibility status.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.636 to 1.134
	Parameter Dispersion	Type: Value:
	Estimation Comments	The HR and confidence interval (CI) were calculated using a stratified Cox proportional hazards model, adjusting for visceral metastases and cisplatin eligibility status with ties handled by the Breslow approach.

18. Secondary Outcome

Title	Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Number [percentage of participants]	36.3 10.6%	25.7 7.4%	49.1 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.422 to 0.788
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.253 to 0.485
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

19. Secondary Outcome

Title	Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Description	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Number [percentage of participants]	46.8 13.7%	27.8 8%	48.3 14%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7708
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.639 to 1.394
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.268 to 0.610
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

20. Secondary Outcome

Title	Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Number [percentage of participants]	20.4 6%	22.6 6.5%	50.4 14.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.135 to 0.406
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6195
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.469 to 1.566
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

21. Secondary Outcome

Title	Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population
Description	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. unconfirmed responses are excluded.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).

Outcome Measure Data

Analysis Population Description

Durvalumab Cisplatin Ineligible Population include all patients who had received D monotherapy and were not eligible for cisplatin treatment at baseline (per eCRF).

Arm/Group Title	Monotherapy - PD-L1 High	Monotherapy - PD-L1 Low/Negative	Monotherapy - Total
Arm/Group Description	MEDI4736 (Durvalumab) - PD-L1 high	MEDI4736 (Durvalumab) - PD-L1 low/negative	MEDI4736 (Durvalumab)
Measure Participants	87	56	143
Number [percentage of participants]	23.0 6.7%	17.9 5.2%	21.0 6.1%

22. Secondary Outcome

Title	Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Number [percentage of participants]	41.5 12.1%	31.8 9.2%	55.5 16.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.410 to 0.759
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; 0.267 to 0.500
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

23. Secondary Outcome

Title	Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Description	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Number [percentage of participants]	49.8 14.6%	34.4 9.9%	53.1 15.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4959
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.590 to 1.291
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.305 to 0.679
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

24. Secondary Outcome

Title	Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Number [percentage of participants]	29.2 8.5%	27.7 8%	59.1 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.27
	Confidence Interval	(2-Sided) 95%; 0.160 to 0.448
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8074
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.623 to 1.836
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

25. Secondary Outcome

Title	Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Number [percentage of participants]	38.0 11.1%	28.0 8.1%	50.6 14.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.432 to 0.802
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; 0.270 to 0.512
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.

26. Secondary Outcome

Title	Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Description	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Number [percentage of participants]	47.3 13.8%	30.6 8.8%	48.8 14.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7717
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.639 to 1.394
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.303 to 0.682
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

27. Secondary Outcome

Title	Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Description	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Number [percentage of participants]	24.1 7%	24.1 7%	53.3 15.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; 0.151 to 0.439
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	monotherapy as reference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9692
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.556 to 1.759
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status.

28. Secondary Outcome

Title	Duration of Response (DoR), Full Analysis Set
Description	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Median (Inter-Quartile Range) [Months]	11.1	9.3	5.7

29. Secondary Outcome

Title	Duration of Response (DoR), PD-L1-High Analysis Set
Description	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Median (Inter-Quartile Range) [Months]	10.0	18.5	5.8

30. Secondary Outcome

Title	Duration of Response (DoR), PD-L1-Low/Negative Analysis Set
Description	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time Frame	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Median (Inter-Quartile Range) [Months]	12.9	5.6	5.7

31. Secondary Outcome

Title	Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set
Description	Blood samples were collected to determine the serum concentration of durvalumab.
Time Frame	Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab

Arm/Group Title	Combination Therapy	Monotherapy
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)
Measure Participants	339	343
Week 0 - Predose	NA (NA)	NA (NA)
Week 0 - Postdose	511 (338)	484 (162)
Week 4 - Predose	75.3 (84.4)	78.9 (56.5)
Week 12 - Predose	125 (97.7)	144 (82.5)
Week 12 - Postdose	594 (298)	576 (233)
Week 24 - Predose	150 (94.4)	163 (82.5)
Week 24 - Postdose	604 (249)	600 (244)
Follow-up Month 3	23.3 (50)	19.9 (18.4)

32. Secondary Outcome

Title	Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set
Description	Blood samples were collected to determine the serum concentration of tremelimumab.
Time Frame	Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab

Arm/Group Title	Combination Therapy
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab
Measure Participants	339
Week 0 - Predose	NA (NA)
Week 0 - Postdose	24.0 (11.5)
Week 4 - Predose	3.75 (3.18)
Week 12 - Predose	5.43 (4.01)
Week 12 - Postdose	28.1 (13.2)
Follow-up Month 3	0.943 (1.40)

33. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients
Description	Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time Frame	At week 0, 4, 12 and 24, and at follow-up Month 3.

Outcome Measure Data

Analysis Population Description

ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result

Arm/Group Title	Combination Therapy	Monotherapy
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)
Measure Participants	340	345
ADA evaluable patients	293 85.7%	302 87.3%
ADA positive at any visit (ADA Prevalence)	37 10.8%	31 9%
Treatment-emergent ADA positive (ADA Incidence)	28 8.2%	11 3.2%
Treatment-boosted ADA	0 0%	1 0.3%
Treatment-induced ADA (Positive Post-baseline only)	28 8.2%	10 2.9%
ADA Positive at Baseline only	8 2.3%	18 5.2%
ADA Positive Post-baseline and Positive at Baseline	1 0.3%	3 0.9%
Persistently Positive	15 4.4%	8 2.3%
Transiently Positive	14 4.1%	5 1.4%
nAb Positive at any visit	3 0.9%	2 0.6%

34. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients
Description	Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time Frame	At week 0, 4, 12 and at follow-up Month 3.

Outcome Measure Data

Analysis Population Description

ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result

Arm/Group Title	Combination Therapy
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab
Measure Participants	340
ADA evaluable patients	292 85.4%
ADA positive at any visit (ADA Prevalence)	64 18.7%
Treatment-emergent ADA positive (ADA Incidence)	54 15.8%
Treatment-boosted ADA	1 0.3%
Treatment-induced ADA (Positive Post-baseline only)	53 15.5%
ADA Positive at Baseline only	8 2.3%
ADA Positive Post-baseline and Positive at Baseline	3 0.9%
Persistently Positive	31 9.1%
Transiently Positive	25 7.3%
nAb Positive at any visit	50 14.6%

35. Secondary Outcome

Title	Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse outcome.
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
NFBLSI - 18 Score (Average overall visits)	-3.7 (0.70)	-3.1 (0.76)	-5.2 (0.82)
FACT-BL TOI (Average overall visits)	-5.5 (0.87)	-3.9 (0.95)	-7.2 (1.02)
FACT-BL Total score (Average overall visits)	-7.2 (1.19)	-4.7 (1.30)	-8.8 (1.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1617
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -0.6 to 3.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0578
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -0.07 to 4.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2003
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; -0.91 to 4.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0178
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; 0.57 to 6.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3765
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -1.96 to 5.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0300
	Comments	MMRM model included patient, treatment, cisplatin eligibility, PD-L1 status and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 0.40 to 7.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
NFBLSI - 18 Score (Average overall visits)	-3.9 (0.85)	-2.0 (0.87)	-5.7 (0.95)
FACT-BL TOI (Average overall visits)	-5.8 (1.09)	-2.6 (1.11)	-8.0 (1.22)
FACT-BL Total score (Average overall visits)	-8.0 (1.47)	-2.7 (1.51)	-10.1 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1373
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -0.6 to 4.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; 1.26 to 6.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1774
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; -1.00 to 5.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.4
	Confidence Interval	(2-Sided) 95%; 2.19 to 8.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3494
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -2.27 to 6.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.3
	Confidence Interval	(2-Sided) 95%; 2.96 to 11.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

37. Secondary Outcome

Title	Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
NFBLSI - 18 Score (Average overall visits)	-3.4 (1.01)	-3.8 (1.18)	-2.0 (1.16)
FACT-BL TOI (Average overall visits)	-4.9 (1.18)	-5.0 (1.39)	-3.0 (1.36)
FACT-BL Total score (Average overall visits)	-5.7 (1.62)	-6.5 (1.90)	-3.2 (1.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3865
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -4.35 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	NFBLSI- 18 score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2840
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -5.05 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2970
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -5.41 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL TOI (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3026
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -5.85 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3168
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -7.29 to 2.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	FACT-BL Total score (Average overall visits)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2179
	Comments	MMRM model included patient, treatment, cisplatin eligibility and visceral metastasis, visit and treatment by visit interaction as explanatory variables, and the appropriate baseline FACT-BL value as a covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 95%; -8.51 to 1.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

38. Secondary Outcome

Title	Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	342	346	344
Patients with improvement in fatigue	38 11.1%	37 10.7%	24 7%
Patient with deterioration in pain	142 41.5%	130 37.6%	83 24.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2419
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.8 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1553
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.9 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; 1.4 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0148
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 1.1 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for PD-L1 status, visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

39. Secondary Outcome

Title	Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: ≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	205	209	207
Patients with improvement in fatigue	23 6.7%	24 6.9%	14 4.1%
Patient with deterioration in pain	78 22.8%	71 20.5%	51 14.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2473
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 0.7 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0148
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; 0.8 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0090
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; 1.2 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1510
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.9 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

40. Secondary Outcome

Title	Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Description	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time Frame	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Outcome Measure Data

Analysis Population Description

The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as: <25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND <25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.

Arm/Group Title	Combination Therapy	Monotherapy	Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab	MEDI4736 (Durvalumab)	Standard of Care Chemotherapy Treatment
Measure Participants	137	137	137
Patients with improvement in fatigue	15 4.4%	13 3.8%	10 2.9%
Patient with deterioration in pain	64 18.7%	59 17.1%	32 9.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6763
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.5 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patients with improvement in fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6539
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.5 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0092
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; 1.2 to 4.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard of Care, Standard of Care
	Comments	Patient with deterioration in pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0324
	Comments	P-value was based on twice the change in log-likelihood resulting from logistic regression model, adjusting for visceral metastases and cisplatin eligibility status.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; 1.1 to 3.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	The OR and confidence interval (CI) were calculated using logistic regression, adjusting for visceral metastases and cisplatin eligibility status, with 95% CI calculated by profile likelihood.

Adverse Events

Time Frame	From first administration of study treatment up to 90 days after last dose of study medication or date of initiation of the first subsequent therapy, whichever occurs first, approximately 5 years. All-cause mortality, from screening up to data cut-off date (27JAN2020, approximately 5 years).
Arm/Group Title	Combination Therapy		Monotherapy		Standard of Care
Arm/Group Description	MEDI4736 (Durvalumab) + Tremelimumab		MEDI4736 (Durvalumab)		Standard of Care Chemotherapy Treatment
All Cause Mortality
	Combination Therapy		Monotherapy		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	255/342 (74.6%)		263/346 (76%)		270/344 (78.5%)
Serious Adverse Events
	Combination Therapy		Monotherapy		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	179/340 (52.6%)		139/345 (40.3%)		125/313 (39.9%)
Blood and lymphatic system disorders
Anaemia	2/340 (0.6%)	2	7/345 (2%)	9	9/313 (2.9%)	9
Bone marrow failure	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Febrile neutropenia	1/340 (0.3%)	1	0/345 (0%)	0	4/313 (1.3%)	4
Haematotoxicity	0/340 (0%)	0	0/345 (0%)	0	3/313 (1%)	4
Leukopenia	0/340 (0%)	0	0/345 (0%)	0	3/313 (1%)	3
Neutropenia	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Pancytopenia	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Thrombocytopenia	0/340 (0%)	0	0/345 (0%)	0	6/313 (1.9%)	6
Cardiac disorders
Acute coronary syndrome	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Acute myocardial infarction	0/340 (0%)	0	3/345 (0.9%)	4	0/313 (0%)	0
Angina pectoris	0/340 (0%)	0	1/345 (0.3%)	1	1/313 (0.3%)	1
Atrial fibrillation	2/340 (0.6%)	2	1/345 (0.3%)	1	2/313 (0.6%)	2
Cardiac arrest	0/340 (0%)	0	3/345 (0.9%)	3	3/313 (1%)	3
Cardiac failure	1/340 (0.3%)	1	0/345 (0%)	0	1/313 (0.3%)	1
Cardiac failure acute	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Cardiac failure chronic	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Cardio-respiratory arrest	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Left ventricular dysfunction	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Myocardial infarction	2/340 (0.6%)	2	5/345 (1.4%)	5	1/313 (0.3%)	1
Myocarditis	0/340 (0%)	0	2/345 (0.6%)	2	0/313 (0%)	0
Stress cardiomyopathy	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Supraventricular tachycardia	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Endocrine disorders
Adrenal insufficiency	3/340 (0.9%)	3	0/345 (0%)	0	0/313 (0%)	0
Hyperthyroidism	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hypophysitis	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Hypopituitarism	4/340 (1.2%)	4	0/345 (0%)	0	0/313 (0%)	0
Hypothyroidism	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Thyroiditis	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Eye disorders
Retinal detachment	0/340 (0%)	0	2/345 (0.6%)	2	0/313 (0%)	0
Gastrointestinal disorders
Abdominal hernia	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Abdominal pain	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Colitis	7/340 (2.1%)	7	0/345 (0%)	0	0/313 (0%)	0
Colonic fistula	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Constipation	7/340 (2.1%)	8	3/345 (0.9%)	3	1/313 (0.3%)	1
Diarrhoea	16/340 (4.7%)	18	2/345 (0.6%)	2	4/313 (1.3%)	4
Duodenitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Enteritis	2/340 (0.6%)	3	0/345 (0%)	0	0/313 (0%)	0
Enterocolitis	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Enterovesical fistula	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Gastric ulcer	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Gastritis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Gastritis erosive	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Gastrointestinal haemorrhage	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Haemorrhoidal haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Ileus	2/340 (0.6%)	3	1/345 (0.3%)	1	1/313 (0.3%)	1
Immune-mediated enterocolitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Inguinal hernia	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Intestinal obstruction	3/340 (0.9%)	5	3/345 (0.9%)	3	0/313 (0%)	0
Large intestinal obstruction	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Large intestine perforation	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Lower gastrointestinal haemorrhage	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Melaena	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Nausea	2/340 (0.6%)	2	1/345 (0.3%)	1	3/313 (1%)	3
Pancreatitis	2/340 (0.6%)	2	1/345 (0.3%)	1	0/313 (0%)	0
Pancreatitis acute	1/340 (0.3%)	1	0/345 (0%)	0	1/313 (0.3%)	1
Rectal haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Small intestinal obstruction	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Stomatitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Vomiting	5/340 (1.5%)	5	1/345 (0.3%)	1	4/313 (1.3%)	4
General disorders
Asthenia	0/340 (0%)	0	2/345 (0.6%)	2	0/313 (0%)	0
Chest pain	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Death	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Extravasation	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Fatigue	3/340 (0.9%)	3	1/345 (0.3%)	1	1/313 (0.3%)	1
General physical health deterioration	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Generalised oedema	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hernia pain	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Malaise	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Mucosal inflammation	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Multiple organ dysfunction syndrome	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Non-cardiac chest pain	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Oedema peripheral	2/340 (0.6%)	2	0/345 (0%)	0	1/313 (0.3%)	1
Pain	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Pyrexia	16/340 (4.7%)	19	6/345 (1.7%)	6	13/313 (4.2%)	13
Hepatobiliary disorders
Acute hepatic failure	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Cholecystitis acute	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Cholecystitis chronic	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Cholestasis	0/340 (0%)	0	1/345 (0.3%)	2	0/313 (0%)	0
Drug-induced liver injury	3/340 (0.9%)	3	1/345 (0.3%)	1	0/313 (0%)	0
Hepatic function abnormal	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hepatitis	2/340 (0.6%)	2	2/345 (0.6%)	2	0/313 (0%)	0
Hepatitis cholestatic	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Hepatotoxicity	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Immune-mediated hepatitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Liver abscess	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Immune system disorders
Anaphylactic shock	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Contrast media reaction	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Infections and infestations
Abdominal abscess	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Abscess	1/340 (0.3%)	2	0/345 (0%)	0	0/313 (0%)	0
Amoebic dysentery	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Anal abscess	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Appendicitis	1/340 (0.3%)	2	1/345 (0.3%)	1	0/313 (0%)	0
Bacteraemia	2/340 (0.6%)	2	0/345 (0%)	0	1/313 (0.3%)	1
Bronchitis	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Cellulitis	0/340 (0%)	0	2/345 (0.6%)	2	2/313 (0.6%)	2
Clostridium difficile infection	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Cystitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Device related infection	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Device related sepsis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Diverticulitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Encephalitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Enterococcal infection	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Escherichia sepsis	2/340 (0.6%)	3	0/345 (0%)	0	0/313 (0%)	0
Escherichia urinary tract infection	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Gastroenteritis	1/340 (0.3%)	1	0/345 (0%)	0	1/313 (0.3%)	1
Influenza	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Listeriosis	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Lower respiratory tract infection	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Nasopharyngitis	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Oral herpes	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Orchitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Osteomyelitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Otitis media chronic	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Peritonitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Pneumocystis jirovecii pneumonia	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Pneumonia	15/340 (4.4%)	15	8/345 (2.3%)	9	2/313 (0.6%)	2
Pneumonia bacterial	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Pneumonia pneumococcal	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Postoperative wound infection	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Prostatic abscess	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Pseudomonas infection	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Pyelonephritis	3/340 (0.9%)	3	6/345 (1.7%)	7	6/313 (1.9%)	6
Pyelonephritis acute	3/340 (0.9%)	3	1/345 (0.3%)	1	1/313 (0.3%)	1
Pyelonephritis chronic	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	3
Respiratory tract infection	1/340 (0.3%)	1	1/345 (0.3%)	1	3/313 (1%)	3
Scrotal abscess	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Sepsis	3/340 (0.9%)	3	11/345 (3.2%)	11	4/313 (1.3%)	6
Septic shock	3/340 (0.9%)	4	2/345 (0.6%)	2	1/313 (0.3%)	1
Sinusitis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Urethritis	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Urinary tract infection	21/340 (6.2%)	26	17/345 (4.9%)	23	21/313 (6.7%)	28
Urinary tract infection bacterial	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Urinary tract infection pseudomonal	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Urosepsis	7/340 (2.1%)	8	4/345 (1.2%)	4	2/313 (0.6%)	2
Injury, poisoning and procedural complications
Ankle fracture	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Concussion	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Facial bones fracture	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Head injury	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Hip fracture	2/340 (0.6%)	2	2/345 (0.6%)	2	1/313 (0.3%)	1
Post procedural fever	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Post procedural haemorrhage	1/340 (0.3%)	2	0/345 (0%)	0	0/313 (0%)	0
Post-traumatic pain	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Procedural complication	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Procedural haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Radiation pneumonitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Stoma obstruction	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Urostomy complication	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Investigations
Alanine aminotransferase increased	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Amylase increased	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Aspartate aminotransferase increased	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Blood creatine phosphokinase increased	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Blood creatinine increased	2/340 (0.6%)	2	1/345 (0.3%)	1	2/313 (0.6%)	2
Blood sodium decreased	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Cardiac murmur	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Haemoglobin decreased	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Lipase increased	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Liver function test increased	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Neutrophil count decreased	0/340 (0%)	0	0/345 (0%)	0	4/313 (1.3%)	4
Oxygen saturation decreased	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Platelet count decreased	0/340 (0%)	0	1/345 (0.3%)	1	6/313 (1.9%)	8
Transaminases increased	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	3/340 (0.9%)	3	1/345 (0.3%)	1	1/313 (0.3%)	1
Dehydration	2/340 (0.6%)	2	1/345 (0.3%)	1	2/313 (0.6%)	2
Diabetes mellitus	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Diabetic ketoacidosis	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Glucose tolerance impaired	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Gout	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	2
Hypercalcaemia	1/340 (0.3%)	1	1/345 (0.3%)	1	1/313 (0.3%)	1
Hypercreatininaemia	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Hyperglycaemia	1/340 (0.3%)	1	2/345 (0.6%)	2	0/313 (0%)	0
Hyperkalaemia	0/340 (0%)	0	2/345 (0.6%)	2	0/313 (0%)	0
Hypernatraemia	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hypoglycaemia	3/340 (0.9%)	3	0/345 (0%)	0	1/313 (0.3%)	1
Hyponatraemia	0/340 (0%)	0	1/345 (0.3%)	1	1/313 (0.3%)	1
Type 2 diabetes mellitus	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/340 (0%)	0	3/345 (0.9%)	3	0/313 (0%)	0
Arthritis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Autoimmune arthritis	0/340 (0%)	0	1/345 (0.3%)	2	0/313 (0%)	0
Back pain	3/340 (0.9%)	3	1/345 (0.3%)	1	0/313 (0%)	0
Bone pain	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Flank pain	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Groin pain	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Musculoskeletal chest pain	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Myopathy	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Myositis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Osteoarthritis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Pain in extremity	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	2/340 (0.6%)	2	0/345 (0%)	0	1/313 (0.3%)	1
Basal cell carcinoma	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Bladder cancer	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Cholangiocarcinoma	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Colon cancer	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Hepatic cancer	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Meningioma	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Neuroendocrine carcinoma	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Oesophageal carcinoma	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Prostate cancer	1/340 (0.3%)	1	0/345 (0%)	0	1/313 (0.3%)	1
Renal adenoma	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Renal neoplasm	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Transitional cell carcinoma recurrent	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Nervous system disorders
Cerebellar infarction	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Cerebral haemorrhage	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Cerebral infarction	0/340 (0%)	0	1/345 (0.3%)	1	1/313 (0.3%)	1
Cerebral ischaemia	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Cerebral thrombosis	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Cerebrovascular accident	3/340 (0.9%)	3	2/345 (0.6%)	2	2/313 (0.6%)	2
Encephalopathy	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Extrapyramidal disorder	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Facial paralysis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Immune-mediated neuropathy	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Ischaemic stroke	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Lethargy	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Loss of consciousness	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Migraine	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Myasthenia gravis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Myasthenic syndrome	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Myoclonus	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Presyncope	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Somnolence	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Syncope	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Product Issues
Device dislocation	1/340 (0.3%)	1	0/345 (0%)	0	1/313 (0.3%)	1
Device occlusion	1/340 (0.3%)	1	2/345 (0.6%)	2	2/313 (0.6%)	2
Psychiatric disorders
Completed suicide	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Confusional state	2/340 (0.6%)	2	1/345 (0.3%)	1	1/313 (0.3%)	1
Delirium	0/340 (0%)	0	2/345 (0.6%)	2	0/313 (0%)	0
Depression	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Psychotic disorder	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Renal and urinary disorders
Acute kidney injury	6/340 (1.8%)	6	5/345 (1.4%)	5	8/313 (2.6%)	9
Azotaemia	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Bladder pain	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Bladder tamponade	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Chronic kidney disease	1/340 (0.3%)	2	1/345 (0.3%)	1	0/313 (0%)	0
Cystitis noninfective	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Dysuria	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Haematuria	3/340 (0.9%)	3	2/345 (0.6%)	2	4/313 (1.3%)	4
Hydronephrosis	4/340 (1.2%)	4	2/345 (0.6%)	2	2/313 (0.6%)	2
Nephritis	1/340 (0.3%)	1	2/345 (0.6%)	2	0/313 (0%)	0
Nephrolithiasis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Obstructive nephropathy	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Oliguria	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Postrenal failure	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Renal failure	4/340 (1.2%)	4	3/345 (0.9%)	3	1/313 (0.3%)	1
Renal impairment	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Renal vein thrombosis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Ureteric obstruction	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Urinary bladder rupture	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Urinary tract obstruction	2/340 (0.6%)	2	1/345 (0.3%)	1	0/313 (0%)	0
Reproductive system and breast disorders
Penile haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Penile pain	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Uterine haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Vaginal haemorrhage	0/340 (0%)	0	1/345 (0.3%)	1	1/313 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Acute respiratory failure	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Asthma	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Chronic obstructive pulmonary disease	4/340 (1.2%)	6	0/345 (0%)	0	0/313 (0%)	0
Diaphragmatic paralysis	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Dyspnoea	3/340 (0.9%)	3	5/345 (1.4%)	5	1/313 (0.3%)	1
Epistaxis	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Interstitial lung disease	3/340 (0.9%)	3	0/345 (0%)	0	0/313 (0%)	0
Pleural effusion	2/340 (0.6%)	2	0/345 (0%)	0	0/313 (0%)	0
Pleuritic pain	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Pneumonia aspiration	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Pneumonitis	5/340 (1.5%)	5	2/345 (0.6%)	3	0/313 (0%)	0
Pulmonary embolism	4/340 (1.2%)	4	3/345 (0.9%)	3	6/313 (1.9%)	6
Respiratory failure	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Skin and subcutaneous tissue disorders
Drug eruption	0/340 (0%)	0	0/345 (0%)	0	1/313 (0.3%)	1
Rash	1/340 (0.3%)	1	1/345 (0.3%)	1	0/313 (0%)	0
Stevens-Johnson syndrome	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Vascular disorders
Circulatory collapse	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Deep vein thrombosis	3/340 (0.9%)	3	0/345 (0%)	0	2/313 (0.6%)	2
Embolism	0/340 (0%)	0	0/345 (0%)	0	2/313 (0.6%)	2
Extremity necrosis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hypertensive emergency	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Hypertensive urgency	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Hypotension	2/340 (0.6%)	2	1/345 (0.3%)	1	0/313 (0%)	0
Intermittent claudication	0/340 (0%)	0	1/345 (0.3%)	1	0/313 (0%)	0
Peripheral artery thrombosis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Vasculitis	1/340 (0.3%)	1	0/345 (0%)	0	0/313 (0%)	0
Other (Not Including Serious) Adverse Events
	Combination Therapy		Monotherapy		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	306/340 (90%)		312/345 (90.4%)		299/313 (95.5%)
Blood and lymphatic system disorders
Anaemia	51/340 (15%)	53	58/345 (16.8%)	63	163/313 (52.1%)	222
Leukopenia	1/340 (0.3%)	1	1/345 (0.3%)	1	25/313 (8%)	50
Neutropenia	0/340 (0%)	0	1/345 (0.3%)	3	89/313 (28.4%)	187
Thrombocytopenia	1/340 (0.3%)	1	7/345 (2%)	10	47/313 (15%)	64
Ear and labyrinth disorders
Tinnitus	3/340 (0.9%)	3	1/345 (0.3%)	1	19/313 (6.1%)	22
Endocrine disorders
Hyperthyroidism	21/340 (6.2%)	22	10/345 (2.9%)	10	1/313 (0.3%)	1
Hypothyroidism	31/340 (9.1%)	34	23/345 (6.7%)	23	0/313 (0%)	0
Gastrointestinal disorders
Abdominal pain	41/340 (12.1%)	47	37/345 (10.7%)	50	27/313 (8.6%)	31
Abdominal pain upper	19/340 (5.6%)	24	4/345 (1.2%)	4	8/313 (2.6%)	9
Constipation	79/340 (23.2%)	88	66/345 (19.1%)	73	89/313 (28.4%)	113
Diarrhoea	99/340 (29.1%)	146	63/345 (18.3%)	96	55/313 (17.6%)	78
Dry mouth	23/340 (6.8%)	25	17/345 (4.9%)	18	4/313 (1.3%)	4
Dyspepsia	12/340 (3.5%)	12	12/345 (3.5%)	14	18/313 (5.8%)	20
Nausea	58/340 (17.1%)	65	74/345 (21.4%)	88	143/313 (45.7%)	237
Vomiting	56/340 (16.5%)	66	36/345 (10.4%)	46	48/313 (15.3%)	61
General disorders
Asthenia	54/340 (15.9%)	69	40/345 (11.6%)	49	68/313 (21.7%)	106
Fatigue	89/340 (26.2%)	106	98/345 (28.4%)	107	101/313 (32.3%)	127
Malaise	5/340 (1.5%)	5	4/345 (1.2%)	5	19/313 (6.1%)	21
Oedema peripheral	30/340 (8.8%)	39	36/345 (10.4%)	41	27/313 (8.6%)	33
Pyrexia	60/340 (17.6%)	80	50/345 (14.5%)	66	43/313 (13.7%)	63
Infections and infestations
Nasopharyngitis	15/340 (4.4%)	16	18/345 (5.2%)	24	11/313 (3.5%)	13
Urinary tract infection	54/340 (15.9%)	69	58/345 (16.8%)	82	46/313 (14.7%)	57
Investigations
Alanine aminotransferase increased	14/340 (4.1%)	15	19/345 (5.5%)	21	21/313 (6.7%)	24
Aspartate aminotransferase increased	17/340 (5%)	18	15/345 (4.3%)	15	16/313 (5.1%)	21
Blood alkaline phosphatase increased	17/340 (5%)	18	20/345 (5.8%)	22	8/313 (2.6%)	10
Blood creatinine increased	17/340 (5%)	25	27/345 (7.8%)	33	31/313 (9.9%)	37
Lipase increased	23/340 (6.8%)	29	18/345 (5.2%)	33	4/313 (1.3%)	6
Neutrophil count decreased	0/340 (0%)	0	1/345 (0.3%)	1	55/313 (17.6%)	135
Platelet count decreased	3/340 (0.9%)	3	4/345 (1.2%)	4	55/313 (17.6%)	124
Weight decreased	33/340 (9.7%)	34	21/345 (6.1%)	22	18/313 (5.8%)	18
White blood cell count decreased	0/340 (0%)	0	0/345 (0%)	0	29/313 (9.3%)	56
Metabolism and nutrition disorders
Decreased appetite	72/340 (21.2%)	79	66/345 (19.1%)	74	80/313 (25.6%)	102
Hyperglycaemia	18/340 (5.3%)	19	9/345 (2.6%)	12	10/313 (3.2%)	15
Hyperkalaemia	17/340 (5%)	20	18/345 (5.2%)	24	18/313 (5.8%)	27
Hypomagnesaemia	8/340 (2.4%)	10	2/345 (0.6%)	2	21/313 (6.7%)	25
Musculoskeletal and connective tissue disorders
Arthralgia	42/340 (12.4%)	56	36/345 (10.4%)	45	11/313 (3.5%)	14
Back pain	34/340 (10%)	38	41/345 (11.9%)	46	31/313 (9.9%)	34
Pain in extremity	18/340 (5.3%)	21	25/345 (7.2%)	28	22/313 (7%)	23
Nervous system disorders
Dizziness	27/340 (7.9%)	30	15/345 (4.3%)	21	25/313 (8%)	32
Dysgeusia	8/340 (2.4%)	9	10/345 (2.9%)	10	26/313 (8.3%)	30
Headache	20/340 (5.9%)	28	18/345 (5.2%)	18	16/313 (5.1%)	19
Neuropathy peripheral	3/340 (0.9%)	3	5/345 (1.4%)	5	16/313 (5.1%)	17
Psychiatric disorders
Insomnia	25/340 (7.4%)	29	25/345 (7.2%)	25	14/313 (4.5%)	15
Renal and urinary disorders
Haematuria	36/340 (10.6%)	40	39/345 (11.3%)	48	14/313 (4.5%)	15
Respiratory, thoracic and mediastinal disorders
Cough	46/340 (13.5%)	55	35/345 (10.1%)	41	18/313 (5.8%)	20
Dyspnoea	24/340 (7.1%)	25	30/345 (8.7%)	32	27/313 (8.6%)	30
Hiccups	2/340 (0.6%)	2	2/345 (0.6%)	2	23/313 (7.3%)	33
Productive cough	20/340 (5.9%)	23	5/345 (1.4%)	5	10/313 (3.2%)	10
Skin and subcutaneous tissue disorders
Alopecia	9/340 (2.6%)	9	4/345 (1.2%)	4	33/313 (10.5%)	33
Pruritus	93/340 (27.4%)	134	53/345 (15.4%)	71	14/313 (4.5%)	22
Rash	58/340 (17.1%)	77	30/345 (8.7%)	38	15/313 (4.8%)	18
Vascular disorders
Hypertension	19/340 (5.6%)	20	19/345 (5.5%)	20	8/313 (2.6%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.