A Global Study to Assess the Effects of MEDI4736 (Durvalumab), Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer (ARCTIC)

• ClinicalTrials.gov Identifier: NCT02352948
• Recruitment Status: Completed
• First Posted: February 2, 2015
• Results First Posted: April 16, 2019
• Last Update Posted: October 11, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non - Small Cell Lung Cancer NSCLC
• Interventions: Drug: MEDI4736 (durvalumab); Drug: Vinorelbine; Drug: Gemcitabine; Drug: Erlotinib; Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4); Drug: tremelimumab (anti-CTLA4)
• Enrollment: 597

Participant Flow

Recruitment Details	This study was divided into 2 parts, sub-study A (82 centers across Europe, Asia, and North America) and sub-study B (149 centers across Europe, Asia, North America, and South America) conducted between 13 January 2015 and 09 February 2018 (data cut-off date).
Pre-assignment Details	The study had a pre-screening period to determine the programmed cell death ligand 1 (PD-L1) status, followed by a screening period and 12 month treatment period. A total of 595 participants were randomized to either sub-study A [PD-L1 high (>=25% of tumor cell (TC) expressing PD-L1)] or sub-study B [PD-L1 low/neg (<25% of TC expressing PD-L1)].

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: Standard of Care (SoC)	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description	Participants received durvalumab (MEDI4736) 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/meter square (m^2) IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until progression of disease (PD), initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion every 4 weeks (Q4W) for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by every 12 weeks (Q12W) for 24 weeks (up to 9 doses).
Period Title: Overall Study
Started	62	64	174	118	117	60
Received Treatment	62	63	173	110	117	60
Completed Study Treatment	15	0	36	0	23	4
Completed [1]	13	5	45	19	29	11
Not Completed	49	59	129	99	88	49
Reason Not Completed
Death	47	48	114	74	77	44
Lost to Follow-up	1	0	2	1	2	1
Withdrawal by Subject	1	10	11	23	9	4
Eligibility criteria not fulfilled	0	1	0	1	0	0
Other	0	0	2	0	0	0
[1] Completed the Study

Baseline Characteristics

Arm/Group Title		Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab	Total
Arm/Group Description		Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).	Total of all reporting groups
Overall Number of Baseline Participants		62	64	174	118	117	60	595
Baseline Analysis Population Description		Sub-study A and B: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	62 participants	64 participants	174 participants	118 participants	117 participants	60 participants	595 participants
	<50 years	3 4.8%	11 17.2%	16 9.2%	8 6.8%	13 11.1%	4 6.7%	55 9.2%
	>=50 to <65 years	31 50.0%	25 39.1%	79 45.4%	49 41.5%	52 44.4%	27 45.0%	263 44.2%
	>=65 to <75 years	24 38.7%	21 32.8%	64 36.8%	50 42.4%	39 33.3%	24 40.0%	222 37.3%
	>=75 years	4 6.5%	7 10.9%	15 8.6%	11 9.3%	13 11.1%	5 8.3%	55 9.2%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	62 participants	64 participants	174 participants	118 participants	117 participants	60 participants	595 participants
	Female	20 32.3%	16 25.0%	59 33.9%	37 31.4%	44 37.6%	21 35.0%	197 33.1%
	Male	42 67.7%	48 75.0%	115 66.1%	81 68.6%	73 62.4%	39 65.0%	398 66.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	62 participants	64 participants	174 participants	118 participants	117 participants	60 participants	595 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	22 35.5%	23 35.9%	41 23.6%	41 34.7%	34 29.1%	16 26.7%	177 29.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	1 1.6%	3 1.7%	2 1.7%	2 1.7%	1 1.7%	9 1.5%
	White	40 64.5%	40 62.5%	129 74.1%	74 62.7%	79 67.5%	43 71.7%	405 68.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 0.9%	0 0.0%	1 0.2%
	Other	0 0.0%	0 0.0%	1 0.6%	1 0.8%	1 0.9%	0 0.0%	3 0.5%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	The OS was defined as the time from the date of randomization until death due to any cause.
Time Frame	From randomization (Day 1) until death due to any cause, approximately 36 months

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.
Overall Number of Participants Analyzed	62	64	174	118
Median (95% Confidence Interval); Unit of Measure: months
	11.7; (8.2 to 17.4)	6.8; (4.9 to 10.2)	11.5; (8.7 to 14.1)	8.7; (6.5 to 11.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study A: Durvalumab, Sub-study A: SoC
	Comments	For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
	Type of Statistical Test	Other
	Comments	Sub-study A was not powered and thus no formal statistical comparisons were performed.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.93
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: SoC
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.109
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.05
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

2. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	The PFS 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 participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to response evaluation criteria in solid tumours (RECIST) version 1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.
Overall Number of Participants Analyzed	62	64	174	118
Median (95% Confidence Interval); Unit of Measure: months
	3.8; (1.9 to 5.6)	2.2; (1.9 to 3.7)	3.5; (2.3 to 4.6)	3.5; (1.9 to 3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study A: Durvalumab, Sub-study A: SoC
	Comments	For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
	Type of Statistical Test	Other
	Comments	Sub-study A was not powered and thus no formal statistical comparisons were performed.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.04
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: SoC
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.056
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.01
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

3. Secondary Outcome

Title	OS, Contribution of the Components Analysis of Sub-study B
Description	The OS was defined as the time from the date of randomization until death due to any cause.
Time Frame	From randomization (Day 1) until death due to any cause, approximately 36 months

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	174	117	60
Median (95% Confidence Interval); Unit of Measure: months
	11.5; (8.7 to 14.1)	10.0; (7.1 to 13.2)	6.9; (3.9 to 13.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Durvalumab
	Comments	As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.885
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.30
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Tremelimumab
	Comments	As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.153
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.11
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

4. Secondary Outcome

Title	Percentage of Participants Alive at 12 Months (OS12)
Description	The OS12 was defined as the percentage of participants who were alive at 12 months after randomisation per Kaplan-Meier estimate of OS at 12 months.
Time Frame	From randomization (Day 1) up to 12 months

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	62	64	174	118	117	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	49.3; (36.3 to 61.0)	31.3; (20.2 to 43.0)	49.5; (41.7 to 56.7)	38.8; (29.9 to 47.7)	43.6; (34.4 to 52.4)	41.2; (28.7 to 53.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: SoC
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.063
	Comments	The z-test statistic is the ratio of log-transformed ratio of the cumulative hazards in the 2 treatment arms divided by square root of the variance.
	Method	z-test
	Comments	The variance is estimated using the delta method and Greenwood's formula.

5. Secondary Outcome

Title	PFS, Contribution of the Components Analysis of Sub-study B
Description	The PFS 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 participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	174	117	60
Median (95% Confidence Interval); Unit of Measure: months
	3.5; (2.3 to 4.6)	3.1; (1.9 to 3.7)	2.1; (1.8 to 3.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Durvalumab
	Comments	As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.282
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.12
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Tremelimumab
	Comments	As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.92
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

6. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	The ORR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) among ITT participants who had measurable disease at baseline. CR was defined as disappearance of all target lesions (any pathological lymph nodes selected as target lesions must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum of diameters as long as criteria for PD are not met). The ORR was measured using Investigator assessments according to RECIST v1.1.
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants with measureable disease at baseline analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	62	64	174	118	117	60
Measure Type: Number; Unit of Measure: percentage of participants
	35.5	12.5	14.9	6.8	15.4	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study A: Durvalumab, Sub-study A: SoC
	Comments	For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
	Type of Statistical Test	Other
	Comments	Sub-study A was not powered and thus no formal statistical comparisons were performed.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.87
	Confidence Interval	(2-Sided) 95%; 1.61 to 10.10
	Estimation Comments	The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: SoC
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.037
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.43
	Confidence Interval	(2-Sided) 95%; 1.10 to 5.94
	Estimation Comments	The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Durvalumab
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.923
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.89
	Estimation Comments	The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: Tremelimumab
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.109
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.46
	Confidence Interval	(2-Sided) 95%; 0.91 to 8.61
	Estimation Comments	The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.

7. Secondary Outcome

Title	Duration of Response (DoR)
Description	The DoR 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. The DoR was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants with measureable disease at baseline analyzed on an ITT basis. Only participants with objective response were analyzed.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	62	64	174	118	117	60
Median (Inter-Quartile Range); Unit of Measure: months
	9.5; (3.0 to 17.8)	4.8; (1.9 to 7.6)	12.2 [1]; (6.5 to NA)	10.8; (5.6 to 12.2)	10.0 [1]; (4.0 to NA)	4.7 [1]; (2.9 to NA)

[1]

The upper limit of the 75th percentile was not calculated as it was not reached.

8. Secondary Outcome

Title	Percentage of Participants Alive and Progression Free at 6 Months (APF6)
Description	The APF6 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 6 months after randomization per Kaplan-Meier estimate of PFS at 6 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 6 months

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	62	64	174	118	117	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	35.5; (23.9 to 47.3)	24.1; (14.1 to 35.6)	31.5; (24.6 to 38.7)	27.6; (19.0 to 36.7)	27.2; (19.4 to 35.6)	14.5; (6.9 to 24.9)

9. Secondary Outcome

Title	Percentage of Participants Alive and Progression Free at 12 Months (APF12)
Description	The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 12 months after randomization per Kaplan-Meier estimate of PFS at 12 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 12 months.

Outcome Measure Data

Analysis Population Description

Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study A: Durvalumab	Sub-study A: SoC	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	62	64	174	118	117	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	19.4; (10.7 to 30.0)	9.9; (3.8 to 19.3)	20.6; (14.7 to 27.1)	8.0; (3.4 to 15.2)	15.0; (9.1 to 22.3)	7.3; (2.4 to 16.0)

10. Secondary Outcome

Title	Time From Randomisation to Second Progression (PFS2) of Sub-study B
Description	The PFS2 was defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the PFS endpoint or death and determined by local standard clinical practice and have included any of the following: objective radiological, symptomatic progression, or death. PFS2 was reported for sub-study B only.
Time Frame	Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until first progression. Disease then assessed per local practice until 2nd progression. Assessed up to a maximum of approximately 3 years.

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants analyzed on an ITT basis.

Arm/Group Title	Sub-study B: Durvalumab+Tremelimumab	Sub-study B: SoC	Sub-study B: Durvalumab	Sub-study B: Tremelimumab
Arm/Group Description:	Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).	Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).	Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
Overall Number of Participants Analyzed	174	118	117	60
Median (95% Confidence Interval); Unit of Measure: months
	9.1; (6.6 to 12.3)	6.7; (4.7 to 8.9)	8.0; (6.3 to 10.0)	5.7; (3.2 to 10.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sub-study B: Durvalumab+Tremelimumab, Sub-study B: SoC
	Comments	For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.85
	Estimation Comments	Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

Adverse Events

Time Frame	From signature of informed consent up to 90 days after the last dose of durvalumab and/or tremelimumab and 30 days after the last dose of SoC, approximately 15 months.
Adverse Event Reporting Description	Sub-study A and B: Safety analysis set included all participants who received at least 1 dose of randomized treatment. All-cause mortality is defined as death due to any cause (including disease progression) for the entire duration of the study.
Arm/Group Title	Sub-study A: Durvalumab		Sub-study A: SoC		Sub-study B: Durvalumab+Tremelimumab		Sub-study B: SoC		Sub-study B: Durvalumab		Sub-study B: Tremelimumab
Arm/Group Description	Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).		Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.		Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).		Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.		Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).		Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).
All-Cause Mortality
	Sub-study A: Durvalumab		Sub-study A: SoC		Sub-study B: Durvalumab+Tremelimumab		Sub-study B: SoC		Sub-study B: Durvalumab		Sub-study B: Tremelimumab
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	48/62 (77.42%)		55/64 (85.94%)		118/174 (67.82%)		90/118 (76.27%)		83/117 (70.94%)		46/60 (76.67%)
Serious Adverse Events
	Sub-study A: Durvalumab		Sub-study A: SoC		Sub-study B: Durvalumab+Tremelimumab		Sub-study B: SoC		Sub-study B: Durvalumab		Sub-study B: Tremelimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/62 (37.10%)		16/63 (25.40%)		65/173 (37.57%)		28/110 (25.45%)		36/117 (30.77%)		23/60 (38.33%)
Blood and lymphatic system disorders
Anaemia † 1	0/62 (0.00%)	0	2/63 (3.17%)	2	0/173 (0.00%)	0	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
Febrile neutropenia † 1	0/62 (0.00%)	0	5/63 (7.94%)	5	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Neutropenia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Pancytopenia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Thrombocytopenia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Cardiac disorders
Acute myocardial infarction † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Angina pectoris † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Atrial fibrillation † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Cardiac arrest † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Cardiac failure † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	2/173 (1.16%)	2	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Cardiac failure congestive † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Myocardial infarction † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pericarditis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Tachycardia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Endocrine disorders
Adrenal insufficiency † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Glucocorticoid deficiency † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Hypopituitarism † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Inappropriate antidiuretic hormone secretion † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Thyroiditis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Ascites † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Colitis † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	3/173 (1.73%)	4	0/110 (0.00%)	0	0/117 (0.00%)	0	5/60 (8.33%)	5
Diarrhoea † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	3/173 (1.73%)	4	0/110 (0.00%)	0	1/117 (0.85%)	1	7/60 (11.67%)	8
Dysphagia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
Enterocolitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Gastrointestinal toxicity † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Ileus paralytic † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Pancreatitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Small intestinal obstruction † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Subileus † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Vomiting † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	3/173 (1.73%)	3	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
General disorders
Asthenia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Death † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Fatigue † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
General physical health deterioration † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Hyperthermia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Non-cardiac chest pain † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Oedema peripheral † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pain † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Perforation † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Pyrexia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	2/117 (1.71%)	2	0/60 (0.00%)	0
Sudden cardiac death † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	2/173 (1.16%)	2	1/110 (0.91%)	1	2/117 (1.71%)	2	0/60 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	3/173 (1.73%)	3	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Cholangitis † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Cholestasis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Drug-induced liver injury † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Hepatitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Immune system disorders
Cytokine release syndrome † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Infections and infestations
Appendicitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Bacterial sepsis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Bronchitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	1/60 (1.67%)	1
Bronchitis viral † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Campylobacter gastroenteritis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Clostridium difficile colitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	2/60 (3.33%)	2
Escherichia infection † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Gastroenteritis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Infection † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Infectious pleural effusion † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Influenza † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Lower respiratory tract infection † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Pneumocystis jirovecii pneumonia † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pneumonia † 1	4/62 (6.45%)	5	3/63 (4.76%)	3	7/173 (4.05%)	7	2/110 (1.82%)	2	2/117 (1.71%)	2	2/60 (3.33%)	2
Pulmonary sepsis † 1	1/62 (1.61%)	1	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pyelonephritis † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Respiratory tract infection † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
Sepsis † 1	2/62 (3.23%)	2	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Varicella zoster virus infection † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Injury, poisoning and procedural complications
Clavicle fracture † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Femur fracture † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Fractured ischium † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Head injury † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Humerus fracture † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Overdose † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Investigations
Amylase increased † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Blood creatinine increased † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	2	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
C-reactive protein increased † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Transaminases increased † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Dehydration † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Diabetes mellitus inadequate control † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Hypercalcaemia † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Hyperglycaemia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Hypokalaemia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Hyponatraemia † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	2/173 (1.16%)	2	0/110 (0.00%)	0	2/117 (1.71%)	2	0/60 (0.00%)	0
Muscular weakness † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Colorectal cancer † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Tumour pain † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Lymphangiosis carcinomatosa † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Prostate cancer stage IV † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Tumour necrosis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Nervous system disorders
Cerebrovascular accident † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Vocal cord paralysis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Brain oedema † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Cerebral infarction † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Dizziness † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Epilepsy † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Ischaemic stroke † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Seizure † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	1
Syncope † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Transient ischaemic attack † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Product Issues
Device dislocation † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Psychiatric disorders
Mental status changes † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Renal and urinary disorders
Urinary retention † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	2	0/60 (0.00%)	0
Acute kidney injury † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Haematuria † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Renal failure † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Dyspnoea † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	7/173 (4.05%)	7	2/110 (1.82%)	2	2/117 (1.71%)	2	0/60 (0.00%)	0
Pneumothorax † 1	1/62 (1.61%)	1	1/63 (1.59%)	1	2/173 (1.16%)	2	0/110 (0.00%)	0	2/117 (1.71%)	3	1/60 (1.67%)	1
Pneumothorax spontaneous † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	1/60 (1.67%)	2
Pulmonary embolism † 1	2/62 (3.23%)	2	0/63 (0.00%)	0	5/173 (2.89%)	5	1/110 (0.91%)	1	1/117 (0.85%)	1	1/60 (1.67%)	1
Acute respiratory failure † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	1/117 (0.85%)	2	0/60 (0.00%)	0
Bronchial fistula † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Chronic obstructive pulmonary disease † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	2/173 (1.16%)	2	0/110 (0.00%)	0	1/117 (0.85%)	1	0/60 (0.00%)	0
Haemoptysis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	2/173 (1.16%)	2	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
Interstitial lung disease † 1	2/62 (3.23%)	2	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pleural effusion † 1	3/62 (4.84%)	3	0/63 (0.00%)	0	2/173 (1.16%)	2	0/110 (0.00%)	0	1/117 (0.85%)	1	2/60 (3.33%)	2
Pneumonia aspiration † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Pneumonitis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	5/173 (2.89%)	5	1/110 (0.91%)	1	1/117 (0.85%)	1	0/60 (0.00%)	0
Respiratory failure † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	1/173 (0.58%)	1	1/110 (0.91%)	1	1/117 (0.85%)	1	2/60 (3.33%)	2
Skin and subcutaneous tissue disorders
Rash † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Toxic skin eruption † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Vascular disorders
Orthostatic hypotension † 1	0/62 (0.00%)	0	1/63 (1.59%)	1	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Deep vein thrombosis † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Embolism † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Hypotension † 1	1/62 (1.61%)	1	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Internal haemorrhage † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Pelvic venous thrombosis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Shock haemorrhagic † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
Subclavian vein thrombosis † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	0/173 (0.00%)	0	1/110 (0.91%)	1	0/117 (0.00%)	0	0/60 (0.00%)	0
Superior vena cava syndrome † 1	0/62 (0.00%)	0	0/63 (0.00%)	0	1/173 (0.58%)	1	0/110 (0.00%)	0	0/117 (0.00%)	0	0/60 (0.00%)	0
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Sub-study A: Durvalumab		Sub-study A: SoC		Sub-study B: Durvalumab+Tremelimumab		Sub-study B: SoC		Sub-study B: Durvalumab		Sub-study B: Tremelimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/62 (83.87%)		59/63 (93.65%)		139/173 (80.35%)		100/110 (90.91%)		99/117 (84.62%)		48/60 (80.00%)
Blood and lymphatic system disorders
Anaemia † 1	5/62 (8.06%)	5	17/63 (26.98%)	22	17/173 (9.83%)	18	27/110 (24.55%)	49	11/117 (9.40%)	13	5/60 (8.33%)	5
Leukopenia † 1	0/62 (0.00%)	0	4/63 (6.35%)	8	2/173 (1.16%)	3	7/110 (6.36%)	15	0/117 (0.00%)	0	1/60 (1.67%)	1
Neutropenia † 1	0/62 (0.00%)	0	7/63 (11.11%)	40	3/173 (1.73%)	7	18/110 (16.36%)	48	0/117 (0.00%)	0	1/60 (1.67%)	3
Thrombocytopenia † 1	1/62 (1.61%)	2	5/63 (7.94%)	10	3/173 (1.73%)	6	11/110 (10.00%)	15	4/117 (3.42%)	4	2/60 (3.33%)	2
Endocrine disorders
Hyperthyroidism † 1	2/62 (3.23%)	2	1/63 (1.59%)	1	17/173 (9.83%)	17	0/110 (0.00%)	0	6/117 (5.13%)	7	1/60 (1.67%)	1
Hypothyroidism † 1	6/62 (9.68%)	6	0/63 (0.00%)	0	14/173 (8.09%)	15	1/110 (0.91%)	1	10/117 (8.55%)	11	3/60 (5.00%)	4
Gastrointestinal disorders
Abdominal pain † 1	4/62 (6.45%)	4	4/63 (6.35%)	4	5/173 (2.89%)	5	2/110 (1.82%)	5	2/117 (1.71%)	2	2/60 (3.33%)	2
Abdominal pain upper † 1	1/62 (1.61%)	1	1/63 (1.59%)	1	2/173 (1.16%)	2	4/110 (3.64%)	6	7/117 (5.98%)	7	2/60 (3.33%)	2
Constipation † 1	13/62 (20.97%)	15	15/63 (23.81%)	16	14/173 (8.09%)	15	11/110 (10.00%)	12	15/117 (12.82%)	16	4/60 (6.67%)	4
Diarrhoea † 1	9/62 (14.52%)	13	8/63 (12.70%)	8	36/173 (20.81%)	45	18/110 (16.36%)	26	25/117 (21.37%)	33	16/60 (26.67%)	20
Nausea † 1	11/62 (17.74%)	12	15/63 (23.81%)	20	28/173 (16.18%)	33	22/110 (20.00%)	32	20/117 (17.09%)	25	11/60 (18.33%)	16
Stomatitis † 1	5/62 (8.06%)	6	5/63 (7.94%)	5	10/173 (5.78%)	11	5/110 (4.55%)	6	3/117 (2.56%)	3	1/60 (1.67%)	3
Vomiting † 1	8/62 (12.90%)	8	4/63 (6.35%)	5	17/173 (9.83%)	17	8/110 (7.27%)	13	18/117 (15.38%)	22	7/60 (11.67%)	10
General disorders
Asthenia † 1	6/62 (9.68%)	6	8/63 (12.70%)	17	31/173 (17.92%)	39	17/110 (15.45%)	19	16/117 (13.68%)	21	9/60 (15.00%)	9
Fatigue † 1	10/62 (16.13%)	10	10/63 (15.87%)	16	25/173 (14.45%)	27	24/110 (21.82%)	30	22/117 (18.80%)	24	4/60 (6.67%)	4
Malaise † 1	1/62 (1.61%)	1	4/63 (6.35%)	8	3/173 (1.73%)	3	5/110 (4.55%)	5	8/117 (6.84%)	8	1/60 (1.67%)	1
Non-cardiac chest pain † 1	4/62 (6.45%)	4	2/63 (3.17%)	3	4/173 (2.31%)	4	4/110 (3.64%)	4	2/117 (1.71%)	2	1/60 (1.67%)	1
Oedema peripheral † 1	6/62 (9.68%)	8	3/63 (4.76%)	5	16/173 (9.25%)	17	9/110 (8.18%)	10	8/117 (6.84%)	10	2/60 (3.33%)	3
Pyrexia † 1	9/62 (14.52%)	14	6/63 (9.52%)	8	20/173 (11.56%)	27	23/110 (20.91%)	33	12/117 (10.26%)	15	6/60 (10.00%)	7
Infections and infestations
Influenza † 1	2/62 (3.23%)	3	0/63 (0.00%)	0	3/173 (1.73%)	3	0/110 (0.00%)	0	6/117 (5.13%)	6	1/60 (1.67%)	1
Viral upper respiratory tract infection † 1	3/62 (4.84%)	5	1/63 (1.59%)	1	15/173 (8.67%)	18	5/110 (4.55%)	5	7/117 (5.98%)	8	1/60 (1.67%)	1
Investigations
Alanine aminotransferase increased † 1	1/62 (1.61%)	2	3/63 (4.76%)	3	10/173 (5.78%)	11	10/110 (9.09%)	15	5/117 (4.27%)	9	5/60 (8.33%)	6
Aspartate aminotransferase increased † 1	1/62 (1.61%)	2	2/63 (3.17%)	2	11/173 (6.36%)	12	8/110 (7.27%)	12	2/117 (1.71%)	5	5/60 (8.33%)	6
Blood creatinine increased † 1	2/62 (3.23%)	2	4/63 (6.35%)	4	2/173 (1.16%)	3	3/110 (2.73%)	6	4/117 (3.42%)	5	2/60 (3.33%)	2
Gamma-glutamyltransferase increased † 1	4/62 (6.45%)	5	2/63 (3.17%)	3	4/173 (2.31%)	4	1/110 (0.91%)	1	1/117 (0.85%)	2	1/60 (1.67%)	1
Neutrophil count decreased † 1	2/62 (3.23%)	2	9/63 (14.29%)	33	2/173 (1.16%)	2	18/110 (16.36%)	43	1/117 (0.85%)	1	0/60 (0.00%)	0
Platelet count decreased † 1	1/62 (1.61%)	1	6/63 (9.52%)	8	1/173 (0.58%)	1	8/110 (7.27%)	27	0/117 (0.00%)	0	0/60 (0.00%)	0
Weight decreased † 1	6/62 (9.68%)	7	4/63 (6.35%)	4	14/173 (8.09%)	14	4/110 (3.64%)	4	8/117 (6.84%)	8	4/60 (6.67%)	4
White blood cell count decreased † 1	1/62 (1.61%)	1	6/63 (9.52%)	21	2/173 (1.16%)	2	11/110 (10.00%)	32	1/117 (0.85%)	1	0/60 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	16/62 (25.81%)	19	20/63 (31.75%)	24	34/173 (19.65%)	39	23/110 (20.91%)	24	27/117 (23.08%)	28	12/60 (20.00%)	12
Dehydration † 1	1/62 (1.61%)	1	1/63 (1.59%)	3	1/173 (0.58%)	1	1/110 (0.91%)	1	0/117 (0.00%)	0	4/60 (6.67%)	6
Hyperkalaemia † 1	5/62 (8.06%)	5	1/63 (1.59%)	2	0/173 (0.00%)	0	1/110 (0.91%)	1	4/117 (3.42%)	5	0/60 (0.00%)	0
Hypokalaemia † 1	5/62 (8.06%)	6	3/63 (4.76%)	3	3/173 (1.73%)	3	2/110 (1.82%)	2	8/117 (6.84%)	10	9/60 (15.00%)	10
Musculoskeletal and connective tissue disorders
Arthralgia † 1	7/62 (11.29%)	8	3/63 (4.76%)	3	16/173 (9.25%)	19	2/110 (1.82%)	4	10/117 (8.55%)	10	4/60 (6.67%)	5
Back pain † 1	7/62 (11.29%)	7	6/63 (9.52%)	7	11/173 (6.36%)	13	4/110 (3.64%)	4	14/117 (11.97%)	15	4/60 (6.67%)	4
Musculoskeletal chest pain † 1	3/62 (4.84%)	5	2/63 (3.17%)	2	7/173 (4.05%)	7	2/110 (1.82%)	2	7/117 (5.98%)	7	2/60 (3.33%)	2
Musculoskeletal pain † 1	6/62 (9.68%)	8	4/63 (6.35%)	4	7/173 (4.05%)	10	5/110 (4.55%)	5	12/117 (10.26%)	12	1/60 (1.67%)	1
Myalgia † 1	2/62 (3.23%)	2	3/63 (4.76%)	4	9/173 (5.20%)	9	4/110 (3.64%)	4	5/117 (4.27%)	5	1/60 (1.67%)	1
Pain in extremity † 1	2/62 (3.23%)	2	2/63 (3.17%)	2	9/173 (5.20%)	11	5/110 (4.55%)	5	9/117 (7.69%)	11	6/60 (10.00%)	7
Nervous system disorders
Dizziness † 1	6/62 (9.68%)	6	5/63 (7.94%)	5	9/173 (5.20%)	10	5/110 (4.55%)	6	8/117 (6.84%)	8	3/60 (5.00%)	3
Headache † 1	9/62 (14.52%)	11	7/63 (11.11%)	8	17/173 (9.83%)	19	6/110 (5.45%)	8	8/117 (6.84%)	8	5/60 (8.33%)	6
Psychiatric disorders
Insomnia † 1	7/62 (11.29%)	7	4/63 (6.35%)	4	6/173 (3.47%)	6	5/110 (4.55%)	5	7/117 (5.98%)	7	5/60 (8.33%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	11/62 (17.74%)	12	9/63 (14.29%)	11	25/173 (14.45%)	26	15/110 (13.64%)	16	16/117 (13.68%)	17	6/60 (10.00%)	6
Cough † 1	11/62 (17.74%)	13	5/63 (7.94%)	5	24/173 (13.87%)	29	14/110 (12.73%)	15	15/117 (12.82%)	20	5/60 (8.33%)	5
Haemoptysis † 1	4/62 (6.45%)	8	2/63 (3.17%)	2	6/173 (3.47%)	7	4/110 (3.64%)	4	7/117 (5.98%)	7	1/60 (1.67%)	1
Rhinorrhoea † 1	6/62 (9.68%)	6	1/63 (1.59%)	1	4/173 (2.31%)	4	2/110 (1.82%)	2	1/117 (0.85%)	1	1/60 (1.67%)	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform † 1	3/62 (4.84%)	4	6/63 (9.52%)	6	6/173 (3.47%)	11	4/110 (3.64%)	4	1/117 (0.85%)	1	0/60 (0.00%)	0
Dry skin † 1	0/62 (0.00%)	0	4/63 (6.35%)	4	4/173 (2.31%)	4	5/110 (4.55%)	5	4/117 (3.42%)	6	3/60 (5.00%)	3
Pruritus † 1	7/62 (11.29%)	8	2/63 (3.17%)	2	28/173 (16.18%)	36	5/110 (4.55%)	5	11/117 (9.40%)	12	14/60 (23.33%)	17
Rash † 1	3/62 (4.84%)	4	9/63 (14.29%)	9	14/173 (8.09%)	15	17/110 (15.45%)	17	7/117 (5.98%)	9	9/60 (15.00%)	11
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Medical Science Director
• Organization: AstraZeneca
• Phone: +1 302 885 1180
• EMail: ClinicalTrialTransparency@astrazeneca.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Martin ML, Correll J, Walding A, Ryden A. How patients being treated for non-small cell lung cancer value treatment benefit despite side effects. Qual Life Res. 2022 Jan;31(1):135-146. doi: 10.1007/s11136-021-02882-6. Epub 2021 May 31.

Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. doi: 10.1016/j.annonc.2020.02.006. Epub 2020 Feb 20.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02352948
• Other Study ID Numbers: D4191C00004; 2014-000338-46 ( EudraCT Number )
• First Submitted: January 28, 2015
• First Posted: February 2, 2015
• Results First Submitted: February 7, 2019
• Results First Posted: April 16, 2019
• Last Update Posted: October 11, 2023