A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently With Platinum-based Chemoradiation Therapy in Patients With Locally Advanced, Unresectable NSCLC (Stage III) (PACIFIC2)
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol
Drug Substance
Durvalumab (MEDI4736)
Study Code
D933KC00001
Version
4.0
Date
04 Mar 2020
A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, 
International Study of Durvalumab Given Concurrently with Platinum-based 
Chemoradiation Therapy in Patients with Locally Advanced, Unresectable 
Non-small Cell Lung Cancer (Stage III) (PACIFIC2)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.
Regulatory Agency Identifying Number(s):
EudraCT number:  2017-004397-34
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Disclosure

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VERSION HISTORY
Version 4.0, 04 Mar 2020
Sections:  1.2, 1.3 (Figure 1), 3, 4.2.1, 8.1, 9.1, 9.2, 9.3 (Table 11), 9.4.2.1, 9.4.2.2, 9.4.8, 
9.5, 9.5.1
Updates reflect changes to multiple testing procedure and resulting impact on analysis 
timelines. Objective response rate (ORR) will now be assessed as a key secondary endpoint. 
The timeline for the interim analysis (IA) of the primary endpoint of PFS has been updated to 
occur when approximately 
 events have been observed. In order to ensure adequate 
maturity for the PFS final analysis (FA), the PFS FA will occur when approximately 
 
events have been observed. The first OS IA will occur at the same time of PFS FA, when 
approximately 
 events are expected. The second OS IA will occur when approximately 
 events have been observed. The timepoint for OS FA has also been updated to occur 
when approximately
 events have been observed. The statistical analyses sections have 
been updated accordingly.
Section 2.3.2.1
Updated to align with Investigator Brochure V14 11Feb2019
Section 6.1.1.4:
Section added to clarify procedures and data collection after final data cut off (DCO)
Section 6.3.2:
Language updated for blinded contract research organization not to have access to the 
randomization scheme
Section 8.2 Table 8:
Removed footnote d.  Calculation of Creatinine Clearance is not done by Data Management.
Section 8.3.12:
Updated to align with Investigator Brochure V14 11Feb2019
Section 8.3.13:
Section added to provide guidance on safety data collection after final DCO
Section 8.4.2:
Removed PREGREP (for reporting pregnancy) and PREGOUT (for reporting pregnancy 
outcome) eCRF modules as these eCRF modules are not used.
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Version 3.0, 10 April 2019
Table 1 and 2:
PGIS evaluation: updated timepoints to align with other PRO questionnaires “
 
 (±3 days) after randomisation, then 
 ±1w until 
, at 
 (relative to 
the date of randomisation) then 
±1w thereafter until PFS2.
Section 4.4:
Removed ‘Durvalumab and 
 combo’ as this is not included in this study design.
Section 5.2:
Added clarification to Exclusion Criterion 13: Patients with T4 lesions that invade major 
vascular structures such as pulmonary artery or cardiac tissues are also not eligible.
Table 6: 
Moved footer from table 7 to table 6 as the acronyms are applicable to that table. 
Version 2.0, 10 September 2018
Various Sections – The protocol has been updated to provide better guidance on radiotherapy
Changes to the protocol are summarised below:
Title : Adding study name : PACIFIC2
Objectives : DCR changed from 
 : No scans expected to be collected at 
 
General : Wording updated:  “dual primary endpoint” instead of “co-primary endpoint”
Table 1 : 
-
Addition of assessment schedule for PFS2 : Based on recent experience, we should 
continue assessments for PFS 2 until study discontinuation or death
-
Final visit removed : redundant information already cover in Table 2
-
ePRO : addition of the +/- 3days visit window, changed ePRO collection from “at  
 after PD or IP discontinuation” to “up to PFS 2”
-
Footnote l:  
o
Pre-dose sample collection clarification : to be collected within 60 minutes 
prior infusion
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o
Clarification on time allowed between randomization and first dose. The time 
between randomization and first dose of IP can be up to 3 days maximum 
(based on investigator assessment). Every effort should be made to minimize 
the time between randomization and starting treatment (i.e. on the same day 
after randomization)
-
HOSPAD to be collected until study termination or death instead of PD
Table 2 :
-
Addition of assessment schedule for PFS2
-
ePRO : addition of the +/- 3days visit window, changed ePRO collection from “at  
 after PD or IP discontinuation” to “up to PFS 2”
-
HOSPAD to be collected until study termination or death instead of PD
Table 5 : Study treatments : Induction cycle for the arm Pemetrexed/Carboplatin option 
removed – considered as non relevant. Addition of optional consolidation cycles of full dose 
Paclitaxel/Carboplatin. 
Table 8 : Clinical chemistry: error corrected for Creatinine. “creatinine clearance” has been 
changed to “creatinine”
Table 11 : DCR changed from 
 to 
Table 13 : Rate of CR and Disease control rate analysis updated from “Fisher’s exact” to 
“analysis using CMH” and to be “Summarized by descriptive statistics”, respectively.
Section 4.3.2 : Rationale wording updated
Section 4.4 : Clarification on end of study definition, and guidance in the event that a roll-
over or safety extension study is available at time of the final DCO and database closure
Section 4.4.1 : Wording updated:  Post final DCO - all SAEs will need to be managed 
according to section 8.4.1 regardless of study treatment. Post final DCO - statement of death is 
no longer required. Also updated wording: Patients who are receiving treatment at the time of 
final DCO may continue receiving durvalumab if the Investigator judges that they are gaining 
clinical benefit (placebo option was removed)
Section 5.1 : 
Inclusion criteria 9 : Wording updated to provide more clarity on the extra DLCO requirement
Inclusion criteria 10 : Reference on liver mets removed
Exclusion criteria 4 & 14 : Wording updated to provide clarity on  dividing distant prior 
cancers, prior lung cancer and cancers with overlapping RT fields
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Section 6.1.1.1 : Wording updated on treatment post final DCO
Section 6.1.1.2 : SoC CRT - Induction cycle for the arm Pemetrexed/Carboplatin option 
removed – considered as non relevant. Addition of optional consolidation cycles of full dose 
Paclitaxel(175-200 mg/m2)/Carboplatin(AUC5-6)
Sections 6.3.2 and 6.3.3 : Added clarification on unblinding: Additionally, at the request of 
the Investigator, following discontinuation of IP and RECIST 1.1-defined progression of 
disease plus the additional regularly scheduled follow-up scan the patient can be unblinded
Section 6.3 : Error corrected – all patients will be centrally randomized only
Section 6.3.2 : Clarification on who will provide the unblinded data to IDMC. Also included 
additional clarification language: following discontinuation of IP and RECIST 1.1-defined 
progression of disease plus the additional regularly scheduled follow-up scan the patient can 
be unblinded. In the setting of rapid clinical progression unblinding should be discussed with 
the AstraZeneca Global Study Physician and Study Statistician
Section 6.7 : Wording updated on treatment post final DCO
Section 8.1.3 : Addition of PGIS to the Clinical outcome assessments
Section 8.4.5.1 : Toxicity Management guidelines web link updated – and appendix G - Dose 
Modification and Toxicity Management Guidelines for Immune-mediated, Infusion related, 
and Non Immune-mediated Reactions removed
Section 9 : Separation of OS from the final PFS 
Section 9.2 : Clarification of what would occur in case of PFS IA not positive
Section 9.3.2 : Safety analysis set:  wording changed to “Randomized treatment (durvalumab 
or matching placebo)” instead of “IP”
Section 9.4.1.1 : RECIST 1.1 BICR definition clarified
DCR at 
 updated to DCR at 
 to match the imaging schedule. 
Section 9.4.1.3 :  Updated wording: For the Time to HRQoL/function deterioration (QLQ-
C30) the wording ‘confirmation at a subsequent visit or death’ was included as it is written in 
symptom deterioration.
Section 9.4.2: Table 13 Disease Control Rate updated wording: Summarized by descriptive 
statistics. This was also updated in Section 9.4.2.7 for DCR.
Section 9.4.2.1 : Typo for maturity at PFS final analysis is corrected from 
Section 9.4.2.9 :  PFS2 assessment schedule is updated to match the updated SoA.
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Section 9.4.2.10 : Typo is corrected as OS is not primary endpoint. 
Section 9.4.3 : Language for retreatment summaries is removed as no retreatment is planned  
in the study
Section 9.5.1 : Removal of PFS IA text duplicate. Clarification on what will happened in case 
of PFS IA is not positive. 
Appendix H : Reworked to provide more detail of the Radiation therapy requirements and 
recommendations
Version 1.0, 15 December 2017
Initial creation
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca Standard 
procedures. The Clinical Study Protocol is publicly registered, and the results are disclosed and/or 
published according to the AstraZeneca Global Policy on Bioethics and in compliance with 
prevailing laws and regulations.

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS .....................................................................................7
1.
PROTOCOL SUMMARY .................................................................................13
1.1
Schedule of Activities (SoA)..............................................................................13
1.2
Synopsis.............................................................................................................22
1.3
Schema ..............................................................................................................27
2.
INTRODUCTION .............................................................................................28
2.1
Study rationale ...................................................................................................28
2.2
Background........................................................................................................29
2.2.1
Immunotherapies................................................................................................29
2.2.2
Durvalumab .......................................................................................................30
2.3
Benefit/risk assessment ......................................................................................31
2.3.1
Potential benefits................................................................................................31
2.3.1.1
Durvalumab as a single agent in metastatic NSCLC ...........................................31
2.3.1.2
Durvalumab after completion of CRT in locally advanced NSCLC ....................31
2.3.2
Overall risks.......................................................................................................33
2.3.2.1
Durvalumab .......................................................................................................33
2.3.2.2
Durvalumab after completion of CRT ................................................................34
2.3.2.3
Concurrent immunotherapy and CRT.................................................................34
2.3.3
Overall benefit/risk.............................................................................................35
3.
OBJECTIVES AND ENDPOINTS ....................................................................36
4.
STUDY DESIGN...............................................................................................37
4.1
Overall design....................................................................................................37
4.2
Scientific rationale for study design....................................................................38
4.2.1
Rationale for study endpoints (efficacy) .............................................................38
4.2.2
Rationale for study endpoints (other exploratory endpoints)...............................39
4.2.3
Rationale for treatment duration.........................................................................39
4.3
Justification for dose ..........................................................................................39
4.3.1
Durvalumab monotherapy dose rationale............................................................40
4.3.2
Rationale for fixed dosing ..................................................................................41
4.4
End of study definition.......................................................................................41
4.4.1
Treatment after final overall survival data cutoff ................................................42
5.
STUDY POPULATION.....................................................................................42
5.1
Inclusion criteria ................................................................................................43
5.2
Exclusion criteria ...............................................................................................45

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5.3
Lifestyle restrictions...........................................................................................48
5.4
Screen failures....................................................................................................50
6.
STUDY TREATMENTS ...................................................................................50
6.1
Treatments administered ....................................................................................51
6.1.1
Investigational products .....................................................................................51
6.1.1.1
Durvalumab (MEDI4736) or placebo .................................................................54
6.1.1.2
SoC CRT ...........................................................................................................54
6.1.1.3
Placebo ..............................................................................................................55
6.1.1.4
Post Final Data Cut Off (DCO) ..........................................................................55
6.2
Preparation/handling/storage/accountability .......................................................56
6.2.1
Product preparation of durvalumab.....................................................................56
6.2.2
Preparation of durvalumab doses for administration with an IV bag ...................56
6.2.3
Preparation of placebo for administration with an IV bag ...................................57
6.2.4
Storage and accountability..................................................................................57
6.3
Measures to minimize bias: randomization and blinding.....................................57
6.3.1
Procedures for randomization.............................................................................58
6.3.2
Methods for ensuring blinding............................................................................58
6.3.3
Methods for unblinding the study.......................................................................59
6.4
Treatment compliance ........................................................................................59
6.5
Concomitant therapy..........................................................................................60
6.5.1
Other concomitant treatment ..............................................................................62
6.5.2
Durvalumab drug-drug interactions....................................................................62
6.5.3
Rescue medication .............................................................................................62
6.6
Dose modification..............................................................................................63
6.7
Treatment after the end of the study ...................................................................63
7.
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL...63
7.1
Discontinuation of study treatment.....................................................................63
7.1.1
Procedures for discontinuation of study treatment ..............................................64
7.2
Lost to follow-up................................................................................................64
7.3
Withdrawal from the study.................................................................................65
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................66
8.1
Efficacy assessments..........................................................................................66
8.1.1
Central reading of scans .....................................................................................67
8.1.2
Survival assessments..........................................................................................67
8.1.3
Clinical outcome assessments.............................................................................68
8.1.3.1
EORTC QLQ-C30 and QLQ-LC13....................................................................68
8.1.3.2
PGIS ..................................................................................................................68
8.1.3.3
EQ-5D-5L..........................................................................................................68
8.1.3.4
Administration of patient-reported outcomes questionnaires...............................69
8.2
Safety assessments .............................................................................................69

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8.2.1
Clinical safety laboratory assessments................................................................70
8.2.2
Physical examinations........................................................................................72
8.2.3
Electrocardiograms ............................................................................................72
8.2.4
Vital signs..........................................................................................................73
8.2.5
WHO/ECOG performance status........................................................................74
8.2.6
Other safety assessments ....................................................................................74
8.3
Collection of adverse events...............................................................................75
8.3.1
Method of detecting AEs and SAEs....................................................................75
8.3.2
Time period and frequency for collecting AE and SAE information ...................75
8.3.3
Follow-up of AEs and SAEs...............................................................................76
8.3.4
Adverse event data collection.............................................................................76
8.3.5
Causality collection............................................................................................77
8.3.6
Adverse events based on signs and symptoms ....................................................77
8.3.7
Adverse events based on examinations and tests.................................................78
8.3.8
Hy’s law.............................................................................................................78
8.3.9
Disease progression............................................................................................78
8.3.10
New cancers.......................................................................................................78
8.3.11
Deaths................................................................................................................79
8.3.12
Adverse events of special interest.......................................................................79
8.3.13
Safety data to be collected following the final DCO of the study........................80
8.4
Safety reporting and medical management .........................................................80
8.4.1
Reporting of serious adverse events....................................................................80
8.4.2
Pregnancy ..........................................................................................................81
8.4.2.1
Maternal exposure..............................................................................................81
8.4.2.2
Paternal exposure ...............................................................................................82
8.4.3
Overdose............................................................................................................82
8.4.4
Medication error.................................................................................................82
8.4.5
Management of IP-related toxicities ...................................................................83
8.4.5.1
Durvalumab .......................................................................................................83
8.4.5.2
Standard of care agents.......................................................................................84
8.5
...............................................................................................84
8.5.1
Collection of samples.........................................................................................84
8.5.2
Collection of samples to measure for the presence of 
...............................85
8.5.3
Storage and destruction of 
 samples .....................................................85
8.6
Pharmacodynamics ............................................................................................85
8.7
.............................................................................................................85
8.7.1
Optional exploratory 
 sample.........................................................85
8.8
Biomarkers.........................................................................................................86
8.8.1
Exploratory biomarkers......................................................................................86
8.8.2
Storage, re-use, and destruction of biological samples........................................88
8.8.3
Labeling and shipment of biological samples .....................................................88
8.9
Health economics...............................................................................................89
9.
STATISTICAL CONSIDERATIONS................................................................89
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9.1
Statistical hypotheses .........................................................................................89
9.2
Sample size determination..................................................................................89
9.3
Populations for analyses.....................................................................................90
9.3.1
Full analysis set..................................................................................................91
9.3.2
Safety analysis set ..............................................................................................91
9.3.3
 analysis set......................................................................................91
9.4
Statistical analyses .............................................................................................92
9.4.1
Outcome measures for analysis ..........................................................................92
9.4.1.1
Calculation or derivation of efficacy variables....................................................92
9.4.1.2
Calculation or derivation of safety variables.......................................................96
9.4.1.3
Calculation or derivation of patient-reported outcome variables – EORTC 
QLQ-C30 and QLQ-LC13..................................................................................97
9.4.1.4
Calculation or derivation of patient-reported outcome variables–PGIS ...............99
9.4.1.5
Calculation or derivation of patient-reported health state utility (EQ-5D-5L)......99
9.4.2
Efficacy analyses..............................................................................................100
9.4.2.1
Primary endpoint: Progression-free survival.....................................................101
9.4.2.2
Objective response rate ....................................................................................103
9.4.2.3
Overall survival................................................................................................104
9.4.2.4
Proportion of patients alive at 24 months..........................................................104
9.4.2.5
Rate of complete response................................................................................104
9.4.2.6
Duration of response ........................................................................................105
9.4.2.7
Disease control rate..........................................................................................105
9.4.2.8
Time to death or distant metastasis...................................................................105
9.4.2.9
Time from randomization to second progression (PFS2) ..................................105
9.4.2.10
Patient-reported outcomes: EORTC QLQ-C30 and QLQ-LC13 .......................105
9.4.2.11
Health care resource use...................................................................................106
9.4.3
Safety analyses.................................................................................................107
9.4.4
 analyses......................................................................................................107
9.4.5
 analysis..................................................................................107
9.4.6
 relationships .................................................................107
9.4.7
Biomarker data.................................................................................................107
9.4.8
Methods for multiplicity control.......................................................................107
9.5
Interim analyses ...............................................................................................109
9.5.1
Independent Data Monitoring Committee.........................................................110
10.
REFERENCES ................................................................................................112
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .......................................................................................120
LIST OF TABLES
Table 1
Schedule of assessments for screening and treatment period............................. 15
Table 2
Schedule of assessments for patients who have discontinued study treatment ... 19
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Table 3
Study objectives............................................................................................... 36
Table 4
Highly effective methods of contraception (<1% failure rate)........................... 50
Table 5
Study treatments............................................................................................... 52
Table 6
Prohibited concomitant medications................................................................. 60
Table 7
Supportive medications .................................................................................... 62
Table 8
Clinical chemistry ............................................................................................ 71
Table 9
Hematology...................................................................................................... 71
Table 10 Urinalysis......................................................................................................... 72
Table 11 Summary of outcome variables and analysis populations.................................. 91
Table 12 Visit responses for symptoms and HRQoL....................................................... 98
Table 13 Formal statistical analyses to be conducted and pre-planned sensitivity analyses100
Table 14 Summary of methods of assessment ............................................................... 141
Table 15 Evaluation of target lesions ............................................................................ 146
Table 16 Evaluation of non-target lesions ..................................................................... 147
Table 17 Overall visit response..................................................................................... 148
Table 18 Summary of motion management options, scans for dose calculations, and 
target delineation ........................................................................................... 154
Table 19 Structure names.............................................................................................. 156
Table 20 Target and treatment time compliance criteria ................................................ 157
Table 21 Recommended dose acceptance criteria for OARs.......................................... 157
LIST OF FIGURES
Figure 1 Study design..................................................................................................... 27
Figure 2
109
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................ 121
Appendix B
Adverse event definitions and additional safety information.................... 125
Appendix C
Handling of human biological samples.................................................... 129
Appendix D
.................................................................................................. 132
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Appendix E
Actions required in cases of increases in liver biochemistry and evaluation 
of Hy’s law.................................................................................................... 135
Appendix F
Guidelines for evaluation of objective tumor response using RECIST 1.1 
criteria (Response Evaluation Criteria in Solid Tumors)................................. 138
Appendix G
Radiation therapy: requirements and recommendations........................... 152
Appendix H
Patient-reported outcomes ...................................................................... 159
Appendix I
Abbreviations........................................................................................... 166

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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The procedures for the screening and treatment period in this study are presented in Table 1, and 
the procedures for the follow-up period are presented in Table 2.
For both treatment arms
!
If imaging procedures were performed for alternate reasons prior to signing consent, 
these can be used for screening purposes with consent of the patient. However, all 
screening imaging scans must have been obtained within 28 days prior to 
randomization.
!
Patient-reported outcomes (PROs) and tumor efficacy (Response Evaluation Criteria In 
Solid Tumors [RECIST]) assessment dates are not affected by dose delays and remain 
as originally scheduled, as they are based on the date of randomization (not the date of 
therapy)
!
All other scheduled assessments must be performed relative to the start of the dosing 
cycle such that all laboratory procedures, etc., required for dosing should be performed 
within 3 days prior to dosing.
For durvalumab/placebo treatment
!
Patients may delay dosing under certain circumstances. 
∀
Dosing may be delayed per the Dosing Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1), due to either an immune or a 
non-immune-related adverse event (AE).
∀
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible (see Section 8.4.5).
∀
One cycle is equal to 28 days.
∀
Dosing intervals of subsequent cycles may be shortened as clinically feasible 
in order to gradually align treatment cycles with the schedule of tumor 
efficacy (RECIST) and PRO assessments. Subsequent time between 
2 consecutive doses cannot be less than 22 days, based on the half-life of 
durvalumab (see the current IB for durvalumab). 

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Chemoradiation therapy
!
Patients may delay and subsequently resume dosing per local standard clinical practice 
(see Section 8.4.5).
∀
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will occur as soon as feasible.

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Table 1
Schedule of assessments for screening and treatment period
Screening
C1 a
C2 a
C3 a
C4 a
C5 to PD a, b
For details see 
Section
Week
to -1
0
 ±3 days unless dosing needs to be held for toxicity reasons
Day
 to -1
1
 ±3 days unless dosing needs to be held for toxicity reasons
Informed consent
Informed consent: study procedures
X
5.1
Consent: genetic sample and analysis (optional) c
X
5.1
Study procedures
Physical exam (full)
X
8.2.2
Targeted physical exam (based on symptoms)
Weekly
X
X
X
8.2.2
Vital signs d
X
X
X
X
X
X
8.2.4
ECG e
X
As clinically indicated
8.2.3
Concomitant medications
<------------------------------------------------------------------------------------------------------------------
---->
6.5
Demography, including baseline characteristics and 
tobacco use
X
8.2.2
Brain MRI (preferred) or high-quality brain CT with 
IV contrast
X
8.2.6
Pulmonary function testing f
X
5.1
Eligibility criteria
X
X
5.1, 5.2
Radiation plan collection
X
Appendix G 7.1
Laboratory assessments
Clinical chemistry
X
X g
X h
X h
X h
X h
Table 8
Hematology
X
X g
X h
X h
X h
X h
Table 9
TSH (reflex free T3 or free T4 i)
X
X
X
X
X
X
Table 8
Urinalysis
X
As clinically indicated
Table 10
Hepatitis B and C and HIV
X
8.2.1
Pregnancy test j
X
X
X
X
X
X
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Screening
C1 a
C2 a
C3 a
C4 a
C5 to PD a, b
For details see 
Section
Week
to -1
0
 ±3 days unless dosing needs to be held for toxicity reasons
Day
to -1
1
 ±3 days unless dosing needs to be held for toxicity reasons
8.5
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
8.2.5
AE/SAE assessment m
<------------------------------------------------------------------------------------------------------------>
8.3
Drug accountability
X
All visits
6.2.4
IP administration
Durvalumab/placebo n, o
X
X
X
X
X
6.1
SoC chemotherapy
Dependent on treatment selected; see Table 5
6.1
SoC radiation therapy
5 fractions/week for 
~6 weeks (±3 days) 
(total 60 Gy)
6.1, Appendix G
Other assessments and assays
8.5
8.8
Whole blood for gene expression (PaxGene-RNA 
8.8
8.8
EORTC QLQ-C30 and QLQ-LC13 p
X
 (±3 days) after randomisation, then 
 ±1w 
through 
 (relative to the date of randomisation) and then 
 ±1w 
thereafter (relative to the date of randomisation)
 
8.1.3
PGIS p
X
 (±3 days) after randomisation, then 
 ±1w until 
 
 (relative to the date of randomisation) then 
±1w 
thereafter 
8.1.3
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Screening
C1 a
C2 a
C3 a
C4 a
C5 to PD a, b
For details see 
Section
Week
to -1
0
 ±3 days unless dosing needs to be held for toxicity reasons
Day
 to -1
1
 ±3 days unless dosing needs to be held for toxicity reasons
EQ-5D-5L p
X
 (±3 days) after randomisation, then 
 ±1w through 
 (relative to the date of randomisation ) and then 
 ±1w thereafter 
(relative to the date of randomisation) until PFS2
8.1.3
Health resource use module (HOSPAD)
X
 for the first 
 (relative to the date of randomization) and then 
 
thereafter (relative to the date of randomisation) until study termination or death
8.9
8.8
8.7
Efficacy evaluations
Tumor evaluation (CT or MRI) (RECIST 1.1) b, q
X
On-study tumor assessments begin 
 ±1w after randomization and 
continue 
±1w through 
 (relative to the date of randomization) and 
then q12w ±1w thereafter (relative to the date of randomization) until RECIST 
1.1-defined radiological progression plus an additional regularly scheduled 
follow-up scan. The on-study imaging 
 ±1w after 
randomization, then 
±1w through 
 and then 
 ±1w thereafter 
MUST be followed regardless of any delays in dosing.
8.1
a
These cycles refer to the 
 cycles of administration of durvalumab/placebo.
b
Patients will have baseline scans collected no more than 28 days before the date of randomization and, ideally, should be performed as close as possible to the date of 
randomization. On-study scans will begin 
 ±1w after randomization, then 
 ±1w through 
 (relative to the date of randomization), and then 
 ±1w 
thereafter (relative to the date of randomization) until RECIST 1.1-defined PD, plus an additional follow-up scan is collected if clinically feasible. 
c
The sample for genetic research will be obtained at 
 If, for any reason, the sample is not drawn at 
 it may be taken at 
 
. Only 1 sample should be collected per patient for genetics during the study.
d
Body weight is recorded at each visit along with vital signs.
e
Any clinically significant abnormalities detected require triplicate ECG results.
f
Pulmonary function testing results for up to
 prior toscreening are permitted.
g
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1. Serum or plasma chemistry, 
hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.
h
Samples for laboratory assessment may be obtained more frequently based on the local clinical practice or the Investigator’s discretion.
i
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
j
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of IP (ie, SoC CRT, durvalumab, or placebo) and then every 
. Pregnancy test may occur on Day 1, but results must be available and 
reviewed by the treating physician or Investigator prior to commencing an infusion 
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m
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
n
Results for LFTs, electrolytes, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator prior to 
dosing.
o
Patients with CR, PR, or SD (based on Investigator assessment) at the 16-week tumor evaluation following completion of SoC CRT will continue to receive 
durvalumab/placebo
as consolidation treatment. 
p
Will be administered using a site-based electronic device. It is preferred that PRO questionnaires are completed prior to any other study procedures (following informed 
consent) and before discussion of disease progression to avoid biasing the patient’s responses to the questions.
q
RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest and abdomen (including the entire liver and 
both adrenal glands). Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely. Additional anatomy should be imaged based on 
signs and symptoms of individual patients at baseline and follow-up. The follow-up scan collected after a RECIST 1.1-defined PD should be performed preferably at the next 
(and no later than the next) scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD, and this scan is evaluated using the Tumor Assessment 
Criteria for Scans Following RECIST 1.1-defined PD outlined in 0. If an unscheduled assessment was performed (eg, to investigate clinical signs/symptoms of progression) 
and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next regularly scheduled visit.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. The time between randomization and first dose of IP can be up to 3 days 
maximum (based on Investigator assessment). Every effort should be made to minimize the time between randomization and starting treatment (i.e. on the same day after 
randomization)
; AE  Adverse event; C  Cycle; CR  Complete response; CRT  Chemoradiation therapy; CT  Computerized tomography; ECG  Electrocardiogram; 
ECOG Eastern Cooperative Oncology Group; EORTC  European Organisation for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5-dimension, 5-level health 
state utility index; HIV  Human immunodeficiency virus; IM  Intramuscular; IP  Investigational product; IV  Intravenous; LFT Liver function test; MRI  Magnetic resonance 
imaging; PD  Progressive disease; 
; PR  Partial response; PRO  Patient-reported outcomes;
  Every 
  Every 
  Every 
  Every 
 QLQ-C30 30 item core quality of life questionnaire; QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; 
RECIST Response Evaluation Criteria in Solid Tumors version 1.1; SAE  Serious adverse event; 
; SoC  Standard of care; 
T3 Triiodothyronine; T4  Thyroxine; TSH Thyroid stimulating hormone; WHO  World Health Organization.
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Table 2
Schedule of assessments for patients who have discontinued study treatment
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
(±2 weeks)
For details, 
see Section
Physical examination (full)
X
8.2.2
Vital signs (temperature, respiratory rate, blood 
pressure, and pulse)
X
8.2.4
Weight
X
X
X
X
8.2.4
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.5
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 
; and then at initiation of 
subsequent anticancer therapy b
8.2.5
Second progression assessment d, e
Patients who discontinue study drug following progression will be assessed every 
 for a
second progression (using the patient’s status at first progression as the reference for assessment of
second progression). A patient’s progression status is defined according to local standard clinical
practice and may involve any of the following: objective radiological imaging, symptomatic
progression, or death. 
8.1
Subsequent anticancer therapy c and survival 
status f
X
X
X
X
X
X (every 
 
±2 weeks)
8.1
Hematology
X
X
X
8.2.1
Clinical chemistry
X
X
X
8.2.1
Urinalysis
As clinically indicated
8.2.1
TSH (reflex free T3 or free T4 g)
X
X
X
8.2.1
8.5
8.5
8.8
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Table 2
Schedule of assessments for patients who have discontinued study treatment
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
(±2 weeks)
For details, 
see Section
Circulating soluble factors (plasma)
X
X
X
8.8
EORTC QLQ-C30 and QLQ-LC13 i
 (±3 days) after  randomisation, then 
 ±1w through 
 (relative 
to the date of randomisation) and then 
 ±1w thereafter (relative to the date of randomisation) 
 
8.1.3
PGIS i
 (±3 days) after randomisation, then 
 ±1w until 
, at 
 
(relative to the date of randomisation) then 
±1w thereafter until PFS2
8.1.3
EQ-5D-5L i
 (±3 days) after randomisation, then 
 ±1w through
 (relative to the 
date of  randomisation) and then 
 ±1w thereafter (relative to the date of  randomisation ) until PFS2
8.1.3
Health resource use module (HOSPAD)
 for the first 
 (relative to the date of randomization) and then 
 thereafter (relative to the 
date of randomisation) until study termination or death
8.9
Tumor assessment (CT or MRI) (RECIST 1.1) j
On-study tumor assessments begin 
 ±1w after randomization and continue 
 ±1w through 
 (relative to the date of randomization) and then 
±1w thereafter (relative to the date of 
randomization) until RECIST 1.1-defined radiological progression plus an additional regularly scheduled 
follow-up scan. The on-study imaging schedule of 
 ±1w after randomization, then 
 ±1w 
through 
, and then
 ±1w thereafter MUST be followed regardless of any delays in dosing.
8.1
a
 
b
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such information. In 
addition, WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
c
Details of any treatment for NSCLC (including surgery) post the last dose of IP must be recorded in the eCRF. At minimum, collect the start date and description of the 
subsequent anticancer therapy. 
d
PFS2 assessment will be performed by the Investigator and defined according to local standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death. 
e
For patients who discontinue their assigned IP following progression, available readings of CT/MRI from local practice will be collected from patients’ medical charts while 
information on subsequent anticancer treatment and/or PFS2 is collected.
f
Patients may be contacted in the week following data cutoffs to confirm survival status. Details of any treatment for NSCLC (including surgery) post the last dose of IP must 
be recorded in the eCRF. Every effort should be made to contact patients by telephone to follow and record survival status.
g
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h
 and 
; ±7 days) after treatment with 
 ends. In addition, a final sample for 
 (±7 days) after treatment with 
i
Will be administered using a site-based electronic device. It is preferred that PRO questionnaires are completed prior to any other study procedures (following informed 
consent) and before discussion of disease progression to avoid biasing the patient’s responses to the questions.
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j
Only for patients yet to progress, RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast, of the chest and 
abdomen (including the entire liver and both adrenal glands). Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely. 
Additional anatomy should be imaged based on signs and symptoms of individual patients. The follow-up scan collected after a RECIST 1.1-defined PD should be 
performed preferably at the next (and no later than the next) scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD, and this scan is evaluated 
using the Tumor Assessment Criteria for Scans Following RECIST 1.1-defined PD outlined in 0. If an unscheduled assessment was performed (eg, to investigate clinical 
signs/symptoms of progression) and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits (relative to 
the date of randomization).
; AE  Adverse event; CT  Computerized tomography; ECOG  Eastern Cooperative Oncology Group; eCRF  Electronic case report form; 
EORTC European Organisation for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5-dimension, 5-level health state utility index; IP  Investigational product; 
IV Intravenous; MRI  Magnetic resonance imaging; NSCLC  Non-small cell lung cancer; PD  Progressive disease; PFS2  Time from randomization to second progression; 
; PRO  Patient-reported outcome; 
  Every 
  Every 
  Every 
; QLQ-C30  30 item core quality of life 
questionnaire; QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; RECIST  Response Evaluation Criteria in Solid Tumors; SAE  Serious adverse event; 
T3 Triiodothyronine; T4  Thyroxine; TSH Thyroid stimulating hormone; WHO  World Health Organization.
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1.2
Synopsis
International co-ordinating investigator: 
Department of Radiation Oncology
Washington University School of Medicine
4129 Parkview Place
St. Louis, MO 63110
Tel: 
Protocol title: A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, 
International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation 
Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer 
(Stage III) 
Rationale: Non-small cell lung cancer (NSCLC) represents approximately 80% to 85% of all 
lung cancers, and 30% of patients present with Stage III disease. While concurrent 
chemoradiation therapy (cCRT) has been shown to be superior to radiation alone and sequential 
therapy, the majority of patients inevitably progress (progression-free survival [PFS] of 8 to 
12 months; 5-year overall survival [OS] of approximately 15% to 32%). Chemoradiation therapy 
(CRT)-induced cell death can enhance the ability of the immune system to recognize and 
respond to the tumor through enhanced antigen release and presentation that, in turn, aids in the 
priming of immune cells to recognize and eliminate tumor cells. Therefore, triggering or 
augmenting an antigenic antitumor response with CRT and combining this treatment with 
anti-programmed cell death ligand 1 (PD-L1) therapy, such as durvalumab, which acts to 
preserve ongoing immune responses by blocking an immunosuppressive signal, theoretically 
may result in enhanced antitumor activity by improving local control and decreasing systemic 
spread. In the PACIFIC study, 1 year of durvalumab as consolidation therapy after achieving 
stable disease (SD) or better with cCRT demonstrated a PFS benefit of 11.2 months over placebo 
in patients with Stage III unresectable NSCLC. Initiating durvalumab during cCRT may further 
enhance outcomes and may provide benefit to those that were never eligible for the PACIFIC 
study due to disease progression prior to randomization.
Objectives and endpoints
Primary objective:
Endpoint/variables:
To assess the efficacy of durvalumab + SoC CRT 
compared with placebo + SoC CRT in terms of 
PFS
PFS using BICR assessments according to 
RECIST 1.1 a
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Objectives and endpoints
Secondary objectives:
Endpoint/variables:
To further assess the efficacy of durvalumab + 
SoC CRT compared with placebo + SoC CRT in 
terms of ORR, OS, OS24, rate of CR, DoR, 
 
, PFS2, and TTDM
ORR using BICR assessments according to RECIST 
1.1
OS and OS24
Rate of CR, DoR, DCR, and TTDM using BICR 
assessments according to RECIST 1.1
 as defined by local standard clinical practice
To assess symptoms and health-related QoL in 
patients treated with durvalumab + SoC CRT 
compared with placebo + SoC CRT using EORTC 
QLQ-C30 v3 and QLQ-LC13
EORTC QLQ-C30 and QLQ-LC13: Change in 
symptoms, functioning, and global health 
status/QoL
Safety objective:
Endpoint/variables:
To assess the safety and tolerability profile of 
durvalumab + SoC CRT compared with placebo 
+ SoC CRT
AEs, physical examinations, vital signs including 
blood pressure, pulse, electrocardiograms, and 
laboratory findings including clinical chemistry, 
hematology, and urinalysis
Exploratory objectives:
Endpoint/variables:
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Objectives and endpoints
a
PFS will be based on programmatically derived PFS by BICR assessment according to RECIST 1.1. See statistical methods 
section for further details.
; AE  Adverse event; BICR  Blinded Independent Central Review; CR Complete response; 
CRT Chemoradiation therapy; 
; DoR  Duration of response; EORTC 
European Organisation for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5 dimension, 5-level health state utility 
index; IP  Investigational product; LC13  Lung Cancer Module; ORR Objective response rate; OS  Overall survival; 
OS24 Proportion of patients alive at 24 months from randomization; 
; PFS Progression-free 
survival; 
  Time from 
; PGIS Patients’ Global Impression of Severity; 
(s); QLQ-C30 30-item core quality of life questionnaire; QoL Quality of life; RECIST  Response 
Evaluation Criteria In Solid Tumors; SoC  Standard of care; TTDM  Time to death or distant metastasis.
Overall design:
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center, international 
study assessing the efficacy and safety of durvalumab given concurrently with platinum-based 
CRT (durvalumab + standard of care [SoC] CRT) in patients with locally advanced, unresectable 
NSCLC (Stage III).
Study period:
Estimated date of first patient enrolled: 
Estimated date of last patient completed:
Number of patients: Approximately 
 patients with locally advanced, unresectable NSCLC 
(Stage III) will be recruited and 300 patients randomized in a 2:1 ratio to durvalumab + SoC 
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CRT or placebo + SoC CRT. Patients will be stratified by age 
 and stage 
 
. 
Treatments and treatment duration: 
All patients will receive 1 of the following platinum-based SoC chemotherapy options, based on 
Investigator discretion, in addition to radiation therapy: cisplatin/etoposide, 
carboplatin/paclitaxel, pemetrexed/cisplatin, or pemetrexed/carboplatin. Chemotherapy treatment 
regimens are outlined in Table 5.
Patients will also receive durvalumab 
 or placebo every 
 via intravenous 
infusion concurrent with SoC CRT (ie, starting on Cycle 1 Day 1 [±3 days]). Patients with 
complete response (CR), partial response (PR), or SD following completion of SoC CRT will 
continue to receive durvalumab/placebo as consolidation treatment. Patients with 
RECIST 1.1-defined radiological progressive disease at the 16-week tumor evaluation following 
completion of SoC CRT will proceed to follow-up.
Independent Data Monitoring Committee:
An independent data monitoring committee (IDMC) composed of independent experts will be 
convened to confirm the safety and tolerability of the proposed dose and schedule of 
durvalumab + SoC CRT. The first safety review will take place when the 
 
 have completed SoC CRT and have had at least 
 of follow-up. 
The second safety review will take place when the 
 
 and have had at least 
 of follow-up. Safety reviews will 
be carried out by the IDMC in an unblinded manner. After review of the unblinded data, the 
IDMC will make a recommendation on whether the study should continue recruitment as 
planned or hold recruitment.
An additional safety review for 
 patients will take place when 
 
 have completed SoC CRT and had 
 days of follow-up. This review will be carried out 
by the IDMC in an unblinded manner. After review of the unblinded data, the IDMC will make a 
recommendation on whether the study should continue recruitment as planned or hold 
recruitment in 
In addition, the IDMC will meet approximately every 
 thereafter to continue safety 
monitoring. The interim analysis (IA) of the primary objective, PFS and secondary objectives of 
objective response rate (ORR), 
 and the first and second OS 
analyses will also be assessed by the IDMC.
Full details of the IDMC procedures, processes, and IAs can be found in the IDMC Charter.
Statistical methods
The primary objective of this study is to assess the efficacy of durvalumab + SoC CRT compared 
with placebo + SoC CRT in terms of PFS per Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). The key 
secondary endpoints (ie, those included in the multiple testing procedure) are ORR per RECIST 
1.1 as assessed by BICR, OS and OS24. 
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A hierarchical testing procedure will be used to strongly control type I error. 
The study is powered for the primary endpoint of PFS and for the key secondary endpoints of OS
and ORR. 
There are up to analysis timepoints for PFS. The PFS IA will occur when approximately 
 (information fraction of 
 have occurred. It is estimated that this DCO will 
occur 
 after the last patient has been randomized. If the 
 for PFS is not positive, 
the DCO for the PFS final analysis will occur when approximately 
 events have 
occurred. It is estimated that this DCO will occur 
 after the last patient has been 
randomized. 
If the true PFS HR is 
 the study will provide greater than 
 to demonstrate a 
statistically significant PFS effect with a 2-sided significance level of 5%; this translates to a 
 in median PFS over 
 on placebo if PFS is exponentially distributed. The 
smallest treatment effect that would be statistically significant is an 
 at final analysis. 
There are up to analysis timepoints for OS. The 
 will occur at the same time of the 
 if the 
. If the 
, the 
 will 
occur when approximately 
 (information fraction of 
 are reached. If the 
, then the 
 will occur when 
approximately 
 (information fraction of 
 are reached. Similarly, if 
 then the 
 will 
occur when approximately 
 events are reached.
If the true 
, the study will have greater than 
 overall power to demonstrate a 
statistically significant OS effect with a 5% 2-sided significance level; this translates to a 
 benefit in median OS over 
 on placebo if OS is exponentially distributed. 
The smallest treatment difference that would be statistically significant is a HR of 0.74 at final 
analysis.
The study has 
 power to detect a statistically significant difference in 
 with a 2-
sided significance level of 0.5%. This assumes the ORR for the patients randomized to placebo + 
SoC CRT is 
 The smallest treatment effect that would be statistically significant is a 
difference in ORR of 
PFS and OS will be analyzed using a stratified log-rank test adjusting for age 
and stage (
). ORR will be compared between the treatment arms using a Cochran-
Mantel-Haenszel test, stratified by age 
 and stage 
Safety data will be summarized descriptively.
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1.3
Schema
The general study design is summarized in Figure 1.
Figure 1
Study design
CR  Complete response; CRT  Chemoradiation therapy; ECOG Eastern Cooperative Oncology Group; n  Number 
of patients; NSCLC Non-small cell lung cancer; ORR Objective response rate; OS Overall survival; 
PD Progressive disease; PFS Progression-free survival; PR Partial response; SD Stable disease; 
SoC Standard of care; WHO World Health Organization.
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2.
INTRODUCTION
Lung cancer has been the most common cancer in the world for several decades, and by 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers. It was also 
the most common cause of death from cancer, with 1.59 million deaths (19.4% of the total) 
(GLOBOCAN 2012). NSCLC represents approximately 80% to 85% of all lung cancers and 
30% of patients present with Stage III disease. Standard treatment for patients with a good 
performance status (PS) and unresectable Stage III NSCLC had been platinum-based doublet 
chemotherapy and radiotherapy administered concurrently with curative intent (cCRT). A meta-
analysis of concurrent versus sequential CRT demonstrated better outcomes with concurrent 
therapy, but even with cCRT, 5-year overall survival (OS) ranges between 15% and 32% 
(ASTRO 2017, Aupérin et al 2010). More recently, the PACIFIC study (D4191C00001) 
demonstrated that the addition of durvalumab as sequential therapy to platinum-based CRT 
significantly improves PFS (median PFS 16.8 months with durvalumab compared to 5.6 months 
with placebo, HR of 0.52; Antonia et al 2017).
The clinical benefit associated with potentiating the proinflammatory effects of CRT observed in 
the PACIFIC study suggests that giving durvalumab in combination with CRT may yield further 
clinical benefits, including increasing the response rate to CRT, improving the complete response 
(CR) rate, and decreasing the number of patients who progress on CRT. 
2.1
Study rationale
Over the last decade, there has been an increasing interest in studying the therapeutic potential of 
immune therapy for different types of tumors. In particular, non-clinical and clinical studies have 
indicated that blockade of immune checkpoints can have a positive effect on antitumor 
immunity. 
Results of early studies with durvalumab in advanced cancers are consistent with a class effect of 
early and sustained tumor control that has been observed previously with other inhibitors of the 
immune checkpoint pathway. A consistent observation across these studies is the long durability 
of benefits with immune checkpoint inhibitors. For patients who experience an objective 
response, the duration of response (DoR) is significantly longer with immunotherapy than with 
chemotherapy alone. However, not all patients benefit from immune checkpoint inhibitors as 
monotherapy. Hence, studies combining immune checkpoint inhibitors with other established 
treatment regimens, such as CRT, are needed in order to expand the patient population who 
might benefit from immune checkpoint inhibitors.
Radiation and CRT have been shown to induce immunogenic cell death. Cell death, from 
radiation or CRT, enhances the ability of the immune system to recognize and respond to the 
tumor through enhanced antigen release and presentation (tumor specific T-cell activation; 
Formenti and Demaria 2013, Weichselbaum et al 2017). In addition, ionizing radiation causes 
upregulation of various pro-inflammatory signals and cytokines, which play a key role in 
immune regulatory pathway, leading to improved antitumor immunity. Twyman-Saint Victor et 
al also showed that radiation enhanced the diversity of the T-cell receptor repertoire of 
intratumoral T-cells (Twyman-Saint Victor et al 2015). Additionally, both chemotherapy and 

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radiotherapy can up-regulate the expression of PD-L1 (Butts et al 2014, Deng et al 2014, Zhang 
et al 2008b). Given these factors, CRT may confer more sensitivity to PD-L1-directed therapy. 
The results of the PACIFIC study support the hypothesis that durvalumab added after definitive 
CRT would provide clinical benefit by potentiating the pro-inflammatory effects of the definitive 
therapy. However, the PACIFIC study only evaluated patients who had not progressed following 
recently completed CRT. A significant unmet medical need still exists in patients who were not 
eligible for the PACIFIC protocol due to progression during or immediately following CRT. The 
addition of durvalumab at an earlier timepoint may be a way to prevent progression during or 
shortly after CRT. Also, the addition of durvalumab to CRT may increase the depth of responses, 
which could translate into longer term clinical benefit.
Furthermore, there is evidence that suggests added benefit may be derived with checkpoint 
inhibition earlier and in combination with radiation. Verbrugge et al demonstrated that the 
combination of radiation with concomitant and adjuvant anti-programmed cell death 1 (PD-1) 
agent can enhance the release of tumor antigens in animal models, and thus synergistically 
improve the antitumor immunity (Verbrugge et al 2012). In mouse flank tumor models, Deng et 
al showed that combination with an anti-PD-L1 antibody and a single high-dose radiation 
showed substantial tumor regression (Deng et al 2014). Additionally, Dovedi and Illidge showed 
the importance of using radiation therapy concurrently, rather than sequentially, with anti-PD-L1 
treatment in providing long-term tumor control (Dovedi and Illidge 2015). Clinically, the 
addition of a PD-1 directed immunotherapy (pembrolizumab) to chemotherapy demonstrated the 
ability to significantly increase response rates in non-squamous NSCLC patients without 
significantly affecting tolerability (Langer et al 2016), and previous radiotherapy has been shown 
to increase the efficacy of pembrolizumab (Shaverdian et al 2017). This suggests that treatment 
with durvalumab concurrent with CRT could lead to additional depth of response to CRT that 
could be associated with longer-term clinical benefit.
Given this, administering durvalumab earlier and in combination with CRT may have added 
clinical benefit and improve the outcome for more patients.
2.2
Background
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004). 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
Tcell- activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells 
(Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) 
(Okazaki and Honjo 2007). The PD-1 and PD-L1/PD-L2 belong to the family of immune 
checkpoint proteins that act as co-inhibitory factors, which can halt or limit the development of 
T cell response. When PD-L1 binds to PD1, an inhibitory signal is transmitted into the T cell, 
which reduces cytokine production and suppresses -Tcell- proliferation. Tumor cells exploit this 
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PD-L1 is constitutively expressed by B cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly overexpressed on tumor cells or on -nontransformed- cells in 
the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD1 
receptors on the activated -Tcells- leading to the inhibition of cytotoxic T cells. These 
deactivated T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway 
represents an adaptive immune resistance mechanism that is exerted by tumor cells in response 
to endogenous anti-tumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells. This activity overcomes PD-L1-mediated inhibition of antitumor immunity. While 
functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different 
from direct agonism of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the 
PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Iwai et al 
2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008a) with responses that tend to be 
more pronounced in patients with tumors that express PD-L1 (Powles et al 2014, Rizvi et al 
2015, Segal et al 2015). In addition, high mutational burden (eg, in bladder carcinoma; 
Alexandrov et al 2013) may contribute to the responses seen with immune therapy.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) and PD-L1 has promising clinical activity. Ipilimumab was granted United States 
(US) Food and Drug Administration (FDA) approval for the treatment of metastatic melanoma 
and is currently under investigation for several other malignancies, while nivolumab and 
pembrolizumab, two anti-PD-1 agents, and atezolizumab, an anti PD-L1 agent, have been 
granted approvals by agencies such as the US FDA and the European Medicines Agency for the 
treatment of a number of malignancies including metastatic melanoma, squamous and non-
squamous cell non-small-cell lung cancer, squamous cell carcinoma of the head and neck, and 
urothelial carcinoma. In addition, there are data from agents in the anti-PD-1/PD-L1 class 
showing clinical activity in a wide range of tumor types.
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand-2 [PD-L2]) with PD-1 on T cells 
and CD80 (B7.1) on immune cells. It is being developed by AstraZeneca/MedImmune for use in 
the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The 
proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 with 
PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the 

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inhibition of immune responses, including those that may result in tumor elimination. In vitro 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary 
human T cells resulting in the restored proliferation of interferon gamma (IFNγ) (Stewart et al 
2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models 
via a T-celldependent- mechanism (Stewart et al 2015). Based on these data, durvalumab is 
expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting 
the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-
dependent cellular cytotoxicity and complement-dependent cytotoxicity.
To date durvalumab has been given to more than 6000 patients as part of ongoing studies either 
as monotherapy or in combination with other anti-cancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12. Refer to the 
current durvalumab Investigator’s Brochure (IB) for a complete summary of non-clinical and 
clinical information including safety, efficacy, and 
 
2.3
Benefit/risk assessment
The following sections include summaries of the potential benefits and risks associated with 
durvalumab prior to the overall benefit-risk assessment.
2.3.1
Potential benefits
2.3.1.1
Durvalumab as a single agent in metastatic NSCLC
The majority of the safety and efficacy data currently available for durvalumab are based on the 
first-in-human, single-agent study (Study 1108) in patients with advanced solid tumors, the study 
of durvalumab monotherapy in NSCLC (Study D4191C00003 [ATLANTIC]), and the study of 
durvalumab monotherapy in NSCLC following completion of platinum-based chemotherapy 
concurrent with radiation therapy (the PACIFIC study, described in Section 2.3.1.2). Data from 
these studies have demonstrated clinical activity of durvalumab therapy in patients with NSCLC. 
Details pertaining to Study 1108 and ATLANTIC are provided in the durvalumab IB.
2.3.1.2
Durvalumab after completion of CRT in locally advanced NSCLC
The PACIFIC study has demonstrated the efficacy of durvalumab versus placebo in patients with 
locally advanced, unresectable Stage III NSCLC who had completed treatment with at least 
2 cycles of platinum-based chemotherapy concurrent with radiation therapy within 1 to 42 days 
prior to the first dose of IP and had not progressed (Antonia et al 2017). As of the first IA (DCO 
of 13 February 2017) for the PACIFIC study, durvalumab demonstrated a statistically significant 
(HR: 0.52; 95% CI: 0.42, 0.65; p-value <0.0001) and clinically meaningful prolongation of PFS 
(according to Blinded Independent Central Review [BICR] assessment of Response Evaluation 
Criteria in Solid Tumors version 1.1 [RECIST 1.1]) compared with placebo. Durvalumab 
treatment demonstrated a median PFS improvement of 11.2 months when compared with 
placebo; treatment effects were observed early and sustained over time, as supported by the 
estimates of the PFS rates at 12 months (55.9% in the durvalumab group and 35.3% in the 
placebo group) and 18 months (44.2% and 27.0%, respectively). The improvement of PFS is 
supported by the clinical meaningful incremental objective response rate (ORR) of 12% over 
placebo (28.4% in the durvalumab group vs 16.0% in the placebo group; nominal p-value 
<0.001). The responses were durable, with the median DoR not reached in the durvalumab group 
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compared to 13.8 months in the placebo group. Of the patients who demonstrated response to 
durvalumab, 72.8% showed ongoing response at both 12 and 18 months after treatment initiation 
compared with 56.1% and 46.8%, respectively, with placebo. In addition, the median time to 
death or distant metastasis (TTDM) was longer for the durvalumab group compared to the 
placebo group (23.2 months in the durvalumab group, compared to 14.6 months in the placebo 
group; HR: 0.52; 95% confidence interval [CI]: 0.39, 0.69; nominal p-value < 0.0001). The 
frequency of BICR-assessed new lesions was lower in the durvalumab group (20.4%) compared 
with that in the placebo group (32.1%), and the incidence of new brain metastases was also lower 
(5.5% vs 11.0%). In addition, the study achieved statistically significant improvement in overall 
survival at  a planned interim analysis.
Concurrent immunotherapy and chemotherapy
The efficacy of immunotherapy administered concurrently with chemotherapy agents is 
supported by recent results from the KEYNOTE-021 study (pembrolizumab; PD-1 inhibitor), the 
CheckMate 012 study (nivolumab; PD-1 inhibitor), and preliminary results from 
Study D419SC00001 (durvalumab ± tremelimumab, a CTLA-4 inhibitor).
The anti-tumor activity of pembrolizumab administration concurrent with various chemotherapy 
regimens versus chemotherapy (carboplatin-pemetrexed) alone as first-line treatment for NSCLC 
(the KEYNOTE-021 study) demonstrated ORRs of 55% (95% CI: 42, 68) versus 
29% (95% CI: 18, 41), respectively (p=0.0016), with DoRs of at least 6 months in 
92% (95% CI: 73, 98) and 81% (95% CI: 51, 93), respectively (Langer et al 2016).
The antitumor activity of nivolumab administered concurrently with platinum-based doublet 
chemotherapy as first-line treatment for advanced NSCLC (the CheckMate 012 study) 
demonstrated ORRs for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg 
plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 
5 mg/kg plus paclitaxel-carboplatin of 33%, 47%, 47%, and 43%, respectively, and 24-week PFS 
rates of 51%, 71%, 38%, and 51%, respectively (Rizvi et al 2016).
The efficacy of durvalumab ± tremelimumab with standard platinum-based chemotherapy in 
advanced cancers is being generated from 2 ongoing Phase I studies: internal 
Study D419SC00001 (n=6) and a Phase Ib study (NCT02537418) run by the Canadian Cancer 
Trials Group (CCTG). Patients in the CCTG study were treated with durvalumab ± 
tremelimumab at 1 of 4 dose levels concomitantly with either pemetrexed + carboplatin / 
cisplatin followed by pemetrexed consolidation for nonsquamous histology (45 patients) or 
gemcitabine + carboplatin/cisplatin for squamous histology (9 patients). Preliminary results from 
this study indicated that a total of 45 patients (44% male; median age=62 years [range 
 to 
]; 
100% Eastern Cooperative Oncology Group [ECOG] PS ≤1) in the pemetrexed-platinum cohort 
received a total of 346 treatment cycles while 9 patients (78% male; median age=64 years [range 
 to 
]; 100% ECOG PS ≤1) in the gemcitabine-platinum group received a total of 
55 treatment cycles. The ORR was 57.1% (95% CI: 39.4, 73.7) in 35 evaluable patients receiving 
pemetrexed-platinum and 37.5% (95% CI: 8.5, 75.5) in 8 evaluable patients receiving 
gemcitibine-platinum (Juergens et al 2017). 
PPD
PPD
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Concurrent immunotherapy and radiation therapy
Currently, over a dozen clinical studies are evaluating anti-PD-1 and anti-PD-L1 antibodies in 
administration concurrently with (as opposed to after completion of) radiation for cancer 
treatment, but robust efficacy results are not yet available (Weichselbaum et al 2017). Several 
non-clinical studies, as described below, suggest that inhibition of the PD-1/PD-L1 checkpoint 
combined with radiotherapy liberates T cells from immunosuppression, which in turn positively 
alters the tumor microenvironment owing to killing of suppressive cells via cytokine secretion. 
Mouse tumor models have been used to demonstrate the synergistic effect of radiotherapy and 
immunotherapy via checkpoint inhibition in solid tumors (Weichselbaum et al 2017). A 
preliminary non-clinical report from the Drake laboratory indicates that radiotherapy combined 
with anti-PD-1 antibody treatment can result in primary tumor control and an abscopal effect 
(Sharabi et al 2014). More recent data from the same group indicate that this therapy 
combination results in the induction of endogenous antigen-specific immune responses, resulting 
in improved local control in single tumor models of melanoma or breast carcinoma (Sharabi et al 
2015); however, no experiments on the abscopal effect were reported. Dovedi and Illidge 
(Dovedi and Illidge 2015) subsequently noted that the timing of anti-PD-L1 blockade is crucial; 
concurrent radiation and anti-PD-L1 treatment, but not sequential treatment, resulted in 
long-term tumor control, suggesting that concurrent administration of durvalumab and SoC 
radiotherapy may have improved clinical benefit over sequential therapy. 
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against TCs. By stimulating the immune system however, there is the potential for adverse 
effects on other tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune mediated effects can occur in nearly any organ system, 
and are most commonly seen as gastrointestinal adverse events (AEs) such as colitis and 
diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver 
enzyme elevations, skin events such as rash and dermatitis, and endocrinopathies including 
hypo- and hyper-thyroidism.
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus and 
diabetes insipidus, events of hypophysitis/hypopituitarism, and adrenal insufficiency), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/pruritus/dermatitis, 
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, 
pancreatitis, serious infections and other rare or less frequent inflammatory events including 
neuromuscular toxicities (e.g. Guillain Barre syndrome, myasthenia gravis). 

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For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB.
In durvalumab monotherapy clinical studies AEs at an incidence of >20% include events such as 
fatigue, nausea, decreased appetite, dyspnea and cough. Approximately 10% of patients 
discontinued the drug due to AE.  Please see the current version of the IB for a detailed summary 
of the monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5.1).
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB.
2.3.2.2
Durvalumab after completion of CRT
In the PACIFIC study, durvalumab treatment in patients with locally advanced, unresectable 
Stage III NSCLC who had recently completed CRT demonstrated a well tolerated and 
manageable safety profile that was consistent with the established safety profile to date with the 
exception of the events of pneumonitis/radiation pneumonitis (Antonia et al 2017). AEs were 
reported in 96.8% of patients who received durvalumab and 94.9% who received placebo; 
Grade 3 or 4 AEs were reported in 29.9% of patients who received durvalumab and 26.1% who 
received placebo. The most frequently reported Grade 3 or 4 AE was pneumonia (4.4% and 
3.8%, respectively). SAEs were reported in 28.6% and 22.6% of patients, respectively, and 
deaths due to AEs occurred in 4.4% and 5.6% of patients, respectively. Pneumonitis and 
radiation pneumonitis were notable events in multiple AE categories. There was a numerical 
increase in these events in the durvalumab group over placebo (33.9% vs 24.8%, respectively, 
patients with pneumonitis or radiation pneumonitis of any grade), but most of these events were 
low grade and manageable. Grade 3 or 4 pneumonitis was reported in 3.4% and 2.6% of patients 
in the durvalumab and placebo groups, respectively. Clinically important Common Terminology 
Criteria for Adverse Event (CTCAE) Grade 3 and above events were infrequent and balanced 
between the 2 groups. In addition to pneumonitis, the other adverse events of special interest
(AESIs) and immune-mediated adverse events (imAEs) reported in the study were typical of the 
PD-1/PD-L1 class of immunotherapies and were generally manageable and/or reversible with 
appropriate treatment guidelines, which included the use of steroids or endocrine therapy, 
withholding durvalumab until the event resolved, or permanent discontinuation of durvalumab.
2.3.2.3
Concurrent immunotherapy and CRT
Concurrent administration of durvalumab and CRT is 
 
 in patients with advanced 
solid tumors (estimated date of first patient enrolled: 
). Safety 
observations from this study will be used to inform decisions regarding safety monitoring for the 
current proposed study. In addition, an IDMC will assess safety data from the current study
 
 
 
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 and then at least every 6 months thereafter, to ensure 
patient safety. 
Concurrent administration of CRT and other immunotherapies has generally been well tolerated 
to date. 
A retrospective review of patients with metastatic lung cancer treated with PD-1/PD-L1 
inhibitors and radiotherapy demonstrated no new safety signals; rates of AEs, including 
pneumonitis, were comparable between treatment groups (Hwang et al 2017). An ongoing study 
of pembrolizumab administered concurrently with CRT in 27 patients with Stage III-IVB 
squamous cell carcinoma of the head and neck has demonstrated no unexpected toxicities and 
safety generally consistent with CRT administration alone (Powell et al 2017). In addition, 
during an ongoing study of nivolumab administered concurrently with CRT in patients with 
Stage IIIA/B NSCLC, a European Thoracic Oncology Platform IDMC review did not observe 
any additional toxicities compared to CRT alone (ClinicalTrials.gov NCT02434081).
Also, across multiple tumor types, the addition of PD-1/PD-L1 based therapies (including 
durvalumab) to platinum-based chemotherapy has been shown to be tolerable with a manageable 
safety profile and no new safety signals (Rizvi et al 2016, Langer et al 2016, 
Study D419SC00001, NCT02537418).
2.3.3
Overall benefit/risk
The clinical activity associated with potentiating the proinflammatory effects of CRT suggests 
that giving durvalumab in combination with CRT may have clinical benefits, including 
increasing the response rate to CRT, improving the CR rate, and decreasing the number of 
patients who progress on CRT. 
Safety observations to date have demonstrated that concurrent administration of CRT and 
immunotherapy has generally been well tolerated, with toxicities comparable to administration of 
either agent alone. The safety of concurrent administration of durvalumab and CRT is further 
supported by results from the PACIFIC study, which showed that durvalumab administered 
within 42 days of completion of CRT had a well tolerated- and manageable safety profile that 
was consistent with the established safety profile to date.
Therefore, the overall benefit-risk assessment supports the proposed study to evaluate the 
efficacy and safety of concurrent administration of durvalumab and CRT.
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3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/variables:
To assess the efficacy of durvalumab + SoC CRT 
compared with placebo + SoC CRT in terms of 
PFS
PFS using BICR assessments according to 
RECIST 1.1 a
Secondary objectives:
Endpoint/variables:
To further assess the efficacy of durvalumab + 
SoC CRT compared with placebo + SoC CRT in 
terms of ORR, OS, OS24, rate of CR, DoR, DCR, 
 and TTDM
ORR using BICR assessments according to RECIST 
1.1
OS and OS24
Rate of CR, DoR, DCR, and TTDM using BICR 
assessments according to RECIST 1.1
as defined by local standard clinical practice
To assess symptoms and health-related QoL in 
patients treated with durvalumab + SoC CRT 
compared with placebo + SoC CRT using EORTC 
QLQ-C30 v3 and QLQ-LC13
EORTC QLQ-C30 and QLQ-LC13: Change in 
symptoms, functioning, and global health 
status/QoL
Safety objective:
Endpoint/variables:
To assess the safety and tolerability profile of 
durvalumab + SoC CRT compared with placebo 
+ SoC CRT
AEs, physical examinations, vital signs including 
blood pressure, pulse, electrocardiograms, and 
laboratory findings including clinical chemistry, 
hematology, and urinalysis
Exploratory objectives:
Endpoint/variables:
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Table 3
Study objectives
a
PFS will be based on programmatically derived PFS by BICR assessment according to RECIST 1.1. See Section 9.4.1.1 for 
further details.
; AE  Adverse event; BICR  Blinded Independent Central Review; CR Complete response; 
CRT Chemoradiation therapy; 
; DCR  Disease control rate; DoR  Duration of response; 
EORTC European Organisation for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5 dimension, 5-level health 
state utility index; IP  Investigational product; LC13  Lung Cancer Module; ORR Objective response rate; OS  Overall 
survival; OS24 Proportion of patients alive at 24 months from randomization; 
; 
PFS Progression-free survival; 
; PGIS Patients’ Global Impression 
of Severity; 
(s); QLQ-C30 30-item core quality of life questionnaire; QoL Quality of life; RECIST  
Response Evaluation Criteria In Solid Tumors; SoC  Standard of care; TTDM  Time to death or distant metastasis.
4.
STUDY DESIGN
4.1
Overall design
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center, international 
study assessing the efficacy and safety of durvalumab given concurrently with platinum-based 
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CRT (durvalumab + SoC CRT) in patients with locally advanced, unresectable NSCLC (Stage 
III). Patients will be stratified by age 
 and stage (
).
Approximately 
 patients with locally advanced, unresectable NSCLC (Stage III) who are 
eligible to receive platinum-based CRT will be enrolled in order to randomize 300 patients in a 
2:1 ratio to either durvalumab + SoC CRT or placebo + SoC CRT. Patients with CR, partial 
response (PR), or stable disease (SD; based on Investigator assessment) at the 16-week tumor 
evaluation following completion of SoC CRT will continue to receive durvalumab/placebo as 
consolidation treatment. Patients with RECIST 1.1-defined radiological progressive disease (PD) 
will proceed to follow-up.
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1. 
For details on what is included in the efficacy and safety endpoints, see Section 3. 
4.2
Scientific rationale for study design
4.2.1
Rationale for study endpoints (efficacy)
The primary aim of this study is to determine the efficacy of durvalumab (
 mg 
 via 
intravenous [IV] infusion) + SoC CRT compared with placebo + SoC CRT.
PFS may serve as a surrogate endpoint for OS when differences between treatment arms are of 
sufficient magnitude and clinically important (FDA Guidance 2011, Mauguen et al 2013, Pazdur 
2008). In particular, a close association of PFS and OS has been observed in stage III NSCLC. 
However, in the setting of advanced, unresectable NSCLC, the utility of survival as an endpoint 
may be confounded by subsequent therapies. Specifically, there are currently a number of 
molecules targeting the PD-1/PD-L1 pathway in late-stage development in patients with first, 
second, and third line PD-L1-positive and PD-L1-unselected NSCLC. Therefore, PFS will be 
used as the primary endpoint in this study.
The key secondary efficacy endpoints (ie, those included in the multiple testing procedure) of 
OS, OS24 and ORR, and other secondary endpoints including rate of CR, DoR, DCR, time 
 
 and TTDM, will be examined to further evaluate 
the antitumor effect of durvalumab + SoC CRT versus placebo + SoC CRT.
ORR can be a useful endpoint, because it is a direct measure of the drug’s antitumor activity 
(Pazdur 2008). The use of ORR in the setting of advanced, unresectable NSCLC, especially 
when the responses are sustained and durable (a key feature of immunotherapy), is justified 
because it is anticipated that it will serve as an early measure of clinical benefit that may be 
confirmed by the survival endpoints employed in a randomized confirmatory study. Assessing 
ORR (and CR rate) will help ascertain the benefit of adding durvalumab during CRT, versus 
waiting until after CRT. Additionally, for patients treated with immunotherapies, including 
durvalumab, responses appear to be durable, reinforcing the importance of ORR as a likely 
surrogate for clinical benefit.
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The secondary symptoms and overall health-related quality of life (QoL) endpoints, assessed 
using the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core 
quality of life questionnaire, version 3 (QLQ-C30 v3) and the complementary 13-item Lung 
Cancer Quality of Life questionnaire (QLQ-LC13) will show the overall influence of the benefits 
and toxicity of the treatment from a patient’s perspective and will aid in understanding of the 
benefit/risk evaluation. These PRO questionnaires are well established instruments that have 
been previously included in cancer clinical studies.
Antitumor activity will be assessed according to RECIST 1.1 guidelines. The analysis of PFS 
and ORR will be based on programmatically derived PFS and ORR based on BICR assessments. 
Sensitivity analyses will also be performed using data from Site Investigator tumor assessments 
based on RECIST 1.1. 
4.2.2
Rationale for study endpoints (other exploratory endpoints)
Biological samples will be used to explore potential 
 in 
 
which may influence the 
 
Blood samples will be taken to allow for research into 
 and 
 of durvalumab, 
and the relationship between durvalumab 
 exposure and clinical outcomes, efficacy, AEs, 
and/or safety parameters.
The assessment of health economic resource use data and derivation of health state utility will 
provide important information for payers and will be used within economic evaluations of 
durvalumab.
4.2.3
Rationale for treatment duration
Treatment in this study will continue until RECIST 1.1-defined PD, or until another 
discontinuation criterion is met (see Section 7.1). This guidance was supported by data from the 
CheckMate-153 study presented at the 2017 ESMO Congress, which indicated that patients 
treated with nivolumab (an anti-PD-1 agent) until PD showed superior PFS when compared to 
treatment with nivolumab with a 1-year fixed duration (HR: 0.43; 95% CI: 0.25, 0.76), a trend 
toward improved OS, and no new safety signals after 1 year of treatment (Spigel et al 2017). In 
the PACIFIC study, no new safety signals were observed with durvalumab after 6 months of 
treatment. Based on these observations, no new safety signals are expected beyond 1 year of 
treatment with durvalumab, but there exists the potential for additional survival benefit beyond 
1 year of treatment. Treatment will be discontinued following RECIST 1.1-defined progression 
to allow the patient the opportunity to utilize an alternate anticancer treatment.
4.3
Justification for dose
This study will utilize 
 for durvalumab treatment (
 mg 
) + SoC CRT 
followed by durvalumab consolidation (
 mg 
). Based on an average body weight of
 of 
 of durvalumab 
 is equivalent to 
 
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4.3.1
Durvalumab monotherapy dose rationale
A durvalumab dose of 
 is supported by in-vitro data, non-clinical activity, clinical 
, and activity data from 
 
 
Based on available 
 from ongoing 
 with doses ranging 
from 
 to 
 or 
, durvalumab exhibited non-linear (dose dependent) 
 consistent with target-mediated drug disposition. The 
 approached linearity at 
 
 suggesting near complete target saturation (membrane-bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 
 The expected half life with doses 
 is 
approximately 
. A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with 
. A low level of 
 has been observed. No patients have experienced immune-complex disease 
following exposure to durvalumab (For further information on 
 please see the 
current IB). 
Data from 
 
 also show an approximately dose-proportional increase in 
 
exposure for durvalumab over the dose range of 
 durvalumab 
 or 
 (For 
further information on 
 observations in 
 please see the current IB). 
The observed durvalumab 
 data from the combination study were well in line with the 
predicted monotherapy 
 data (5th median and 95th percentiles) for a q4w regimen. 
A population 
 model was developed using the data from 
 (
 to 
 
 or 
 (Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 
 and 
 regimens, as represented 
by the area under the plasma drug concentration-time curve at steady state (AUCss; 
). 
Median Cmax,ss is expected to be higher with 
 (~1.5 fold) and median Ctrough,ss 
is expected to be higher with 
 (~1.25 fold). Clinical activity with the 
 
 dosing regimen is anticipated to be consistent with 
 with the proposed similar 
dose of 
 expected to (a) achieve complete target saturation in majority of patients; 
(b) account for anticipated variability in 
, and clinical activity in diverse 
cancer populations; (c) maintain sufficient 
 exposure in case of 
 
impact; and (d) achieve 
 exposure that yielded maximal antitumor activity in animal models.
Given the similar AUC and modest differences in median peak and trough levels at steady state, 
the observation that both regimens maintain complete sPD-L1 suppression at trough, and the 
available clinical data, the 
 and 
 regimens are expected to have 
similar efficacy and safety profiles, supporting further development with a dose of 
 
. 
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Clinical data
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and 
 at the 
 regimen.
4.3.2
Rationale for 
A population 
 model was developed for durvalumab using monotherapy data 
 
(N=292; doses= 
 to 
 or 
; solid tumors). Population PK analysis 
indicated only minor impact of body weight (WT) on the 
 of durvalumab (coefficient of 
≤0.5). The impact of body WT-based (
) and fixed dosing (
) of 
durvalumab was evaluated by comparing 
 (5th, median, 
and 95th percentiles) using the population PK model.
 
A total of 1000 patients were 
simulated using body WT distribution of 40 to 120 kg.
 
 
 
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang 
et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that 
 
 dosing perform similarly, with 
 being better for 7 of 
12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that 
 performed better for 12 of 18 in terms of reducing the 
between-patient variability in 
 parameters (Zhang et al 2012). 
A 
 approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, we considered 
it feasible to switch to 
 regimens. Based on average body WT of 75 kg, a 
 
of 
 durvalumab (equivalent to 
) is included in the current study.
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the Schedule of Activities (SoA).
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab may be transitioned 
to such a study, and the current study would reach its end. The roll-over or safety extension study 
would ensure treatment continuation with visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new Informed Consent.
See Appendix A, A 6 for guidelines for the dissemination of study results.
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4.4.1
Treatment after final overall survival data cutoff
At the time of the final data cutoff (DCO), the analysis portion of the clinical study will have 
been completed and all patients remaining in the study will be considered to have completed the 
analysis portion of the study. At the time of final analysis, the clinical study database will be 
closed to new data.
Patients in OS follow-up (progressed and have discontinued treatment) will be considered to 
have completed the study. Patients in progression-free follow-up (patients who have 
discontinued study drug treatment and have not progressed) may decide to continue in the study 
in progression-free follow-up.
Patients who are receiving treatment at the time of final DCO may continue receiving 
durvalumab if the Investigator judges that they are gaining clinical benefit.
All patients will receive scans and follow-up care in accordance with standard local clinical 
practice. All data will be recorded on patient charts but will not otherwise be reported for the 
purposes of this study.
For patients who do continue to receive treatment beyond the time of the final DCO, 
Investigators will report serious adverse events (SAEs) to AstraZeneca Patient Safety via paper 
case report forms (CRFs) until 90 days after the last dose of study treatment, in accordance with 
Section 8.4.1. Any non-serious AE that is ongoing at the time of this DCO is to be followed up at 
the discretion of the Investigator and per local practice and in alignment with the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5.1). Data will not be 
captured for the purposes of this study outside of being recorded in the patients’ source 
documents.
Following the final DCO, SAE reporting applies only to patients who are active on durvalumab 
and within 90 days after the last dose. No OS data will be recorded in the study database after 
final DCO for the study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures (refer to Section 5.4).
In this protocol, “enrolled” patients are defined as those who sign an informed consent. 
“Randomized” patients are defined as those who undergo randomization and receive a 
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Investigator(s) should keep a record, the patient screening log, of patients who entered pre-study 
screening.
5.1
Inclusion criteria
Informed consent
1.
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
2.
Provision of signed and dated, written ICF prior to any mandatory study-specific 
procedures, sampling, and analyses. 
The ICF process is described in Appendix A, A 3.
Age
3.
18 years or older at the time of signing the ICF. In Japan, patients must be 20 years or 
older at the time of signing the ICF.
Type of patient and disease characteristics
4.
Histologically or cytologically documented NSCLC who present with locally 
advanced, unresectable (Stage III) disease (according to Version 8 of the International 
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology 
[IASLC Staging Manual in Thoracic Oncology 2016]).
∀
Except for overt cT4 disease, nodal status N2 or N3 should be proven by biopsy, 
via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Absent biopsy, 
nodal status should be confirmed with whole body 18F-fluoro-deoxyglucose 
positron emission tomography, plus contrast-enhanced computed tomography 
(CT) in addition to or in combination with PET.
∀
Mandatory brain magnetic resonance imaging (MRI; preferred) or high-quality 
brain CT with IV contrast at the time of staging.
5.
World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1 at enrollment and randomization.
6.
Patients with at least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 
Target Lesion (TL) at baseline. Tumor assessment by CT or MRI must be performed 
within 
 prior to randomization.
7.
Tumor sample requirements:  
∀
Mandatory provision of an archived tumor tissue block (or at least 
 
 (refer to Section 8.8 and the Laboratory Manual for 
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details). If an archival sample is not available, provision of a recent (≤3 months) 
tumor biopsy is mandated.
∀
The provision of an additional recent 
) tumor biopsy is optional, 
provided that a biopsy procedure is technically feasible and the procedure is not 
associated with unacceptable clinical risk.
8.
Must have a life expectancy of at least 12 weeks at randomization
9.
Adequate pulmonary function test results as described below: 
!
Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or 
>40% predicted value  
And,
!
Diffusing capacity of the lung for carbon monoxide (DLCO) >30% predicted 
value. 
10.
Adequate organ and marrow function at enrollment and randomization as defined 
below:
∀
Hemoglobin ≥9.0 g/dL
∀
Absolute neutrophil count >1.5 × 109/L
∀
Platelet count >100 × 109/L
∀
Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in consultation 
with their physician.
∀
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 × ULN.
∀
Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as 
determined by Cockcroft-Gault (using actual body weight)
Males:
Creatinine CL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL = 
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
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11.
 research study (optional)
For inclusion in the optional 
 research study, patients must fulfil the 
following criteria:
∀
Provide informed consent for the 
 sampling and analyses.
If a patient declines to participate in the 
 research, there will be no penalty or 
loss of benefit to the patient. A patient who declines 
 research participation 
will not be excluded from any other aspect of the main study.
Weight
12.
Body weight >30 kg at enrollment and randomization.
Sex
13.
Male or female
Reproduction
14.
Evidence of post-menopausal status, or negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause. The 
following age-specific requirements apply:
∀
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).
∀
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, 
or hysterectomy).
5.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions
1.
History of allogeneic organ transplantation.
2.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
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Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]). 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 5 years at randomization may be 
included but only after consultation with the study physician
∀
Patients with celiac disease controlled by diet alone
3.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase risk of incurring AEs, or 
compromise the ability of the patient to give written informed consent
4.
History of another primary malignancy except for
∀
Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of IP and of low potential risk for recurrence. 
Patients with a previous history of radiation therapy are eligible provided field 
overlap is minimal and the risk of toxicity to tissues in the overlapping region(s) is 
deemed to be acceptable by treating radiation oncologist. 
∀
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease
∀
Adequately treated carcinoma in situ without evidence of disease
5.
History of leptomeningeal carcinomatosis
6.
History of active primary immunodeficiency.
7.
Active infection including tuberculosis (TB) (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with 
local practice), hepatitis B (known 
] result), 
hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 
antibodies). Patients with a past or resolved HBV infection (defined as the 
 
) are eligible. Patients 
 are eligible only if polymerase chain reaction is 
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8.
Mixed small cell and NSCLC histology.
9.
Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
10.
Any medical contraindication to treatment with platinum-based doublet chemotherapy 
as listed in the local labelling.
11.
Patients whose radiation treatment plans are likely to encompass a volume of whole 
lung receiving ≥20 Gy in total (V20) of more than 35% of lung volume. V20s up to 
37% will be permitted and viewed as a minor deviation, provided that the treating 
radiation oncologist believes this level of exposure is within patient tolerance.
12.
Planned radiation cardiac dose V50 >25%.
13.
Patients who have disease considered for surgical treatment as part of their care plan, 
such as Pancoast or superior sulcus tumors. Patients with T4 lesions that invade major 
vascular structures such as pulmonary artery or cardiac tissues are also not eligible. 
Prior/concomitant therapy
14.
Receipt of prior or current cancer treatment for NSCLC, including but not limited to, 
radiation therapy, investigational agents, chemotherapy, and mAbs. Prior surgical 
resection of metachronus NSCLC (ie, Stage I or II) is permitted. 
15.
Receipt of live attenuated vaccine within 
 prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine while receiving IP and up to 
 after the last dose of IP.
16.
Major surgical procedure (as defined by the Investigator) within 
 prior to the 
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
17.
Prior exposure to immune-mediated therapy, including but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding 
therapeutic anticancer vaccines.
18.
Current or prior use of immunosuppressive medication within 
 before the first 
dose of 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)
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Prior/concurrent clinical study experience
19.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
20.
Previous IP assignment in the present study 
21.
Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study or the follow-up period of an interventional study. 
22.
Participation in another clinical study with an IP during the 
 prior to 
randomization.
23.
Prior randomization or treatment in a previous durvalumab clinical study regardless of 
treatment arm assignment.
Other exclusions
24.
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 
 after the last dose of IP.
25.
Judgment by the Investigator that the patient is unsuitable to participate in the study 
and the patient is unlikely to comply with study procedures, restrictions, and 
requirements.
26.
Genetics research study (optional):
Exclusion criteria for participation in the optional 
 research component 
of the study include:
∀
Previous allogeneic bone marrow transplant.
∀
 in 120 days of 
 
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1.
Female patient of child-bearing potential
∀
Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non sterilized male partner must use at least 1 highly
effective method of contraception (Table 4) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (90 days after 
the last dose of IP). Non sterilized male partners of a female of childbearing 
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potential must use male condom plus spermicide throughout this period. Cessation 
of birth control after this point should be discussed with a responsible physician. 
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. Female patients should also refrain from 
breastfeeding throughout this period.
2.
Male patients with a female partner of childbearing potential
∀
Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 
spermicide from the time of screening throughout the total duration of the drug 
treatment and the drug washout period (90 days after the last dose of IP). 
However, periodic abstinence, rhythm method, and withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm 
donation throughout this period.
∀
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 4).
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
!
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution. 
!
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago.
Highly effective methods of contraception, defined as those that result in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 4. Note 
that some contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 
where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills).
In addition to the guidelines described above, local prescribing information relating to 
contraception, the time limits for such precautions, and any additional restrictions for SoC CRT 
agents must be followed.

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Table 4
Highly effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal methods
!
Copper T intrauterine device
!
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
!
Implants b: Etonogestrel-releasing 
implants: eg, Implanon® or Norplant® 
!
Intravaginal Devices b: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: eg, NuvaRing®  
!
Injection b: Medroxyprogesterone 
injection: eg, Depo-Provera®  
!
Combined Pill: Normal and low dose 
combined oral contraceptive pill
!
Patch b: Norelgestromin/ethinylestradiol-
releasing transdermal system: eg, Ortho 
Evra®  
!
Minipill b: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill
a
This is also considered a hormonal method
b
This hormonal method is not approved in Japan.
3.
All patients: Patients should not donate blood or blood components while participating 
in this study and through 
 after receipt of the final dose of IP, or until alternate 
anticancer therapy is started. 
Restrictions relating to concomitant medications are described in Section 6.5.
5.4
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded as 
“eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (ie, not randomized 
patients). Patients can be rescreened a single time, but they cannot be re-randomized. 
6.
STUDY TREATMENTS
Study treatment is defined as any IPs (including marketed product comparator and placebo) 
intended to be administered to a study participant according to the study protocol. Study 
treatment in this study refers to chemotherapy and radiation (CRT), durvalumab, and placebo.
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6.1
Treatments administered
6.1.1
Investigational products
AstraZeneca/MedImmune will supply durvalumab (MEDI4736). SoC agents (chemotherapy and 
radiation) and the saline solution for the placebo will be supplied locally. Under certain 
circumstances when local sourcing is not feasible, SoC treatment (chemotherapy) may be 
supplied centrally through AstraZeneca. See Table 5 for further details on the IPs.

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Table 5
Study treatments
Durvalumab
Placebo
Standard of carea
Study treatment 
name:
Durvalumab 
(MEDI4736)
Saline 
solution
Cisplatin/ 
Etoposide
Carboplatin/ Paclitaxel
Pemetrexed/ 
Cisplatin b
Pemetrexed/ 
Carboplatin b
Radiation
Dosage 
formulation:c
Sterile 
solution 
of 
for 
injection
As sourced locally
As sourced locally
As 
sourced 
locally
As 
sourced 
locally
As sourced 
locally
Route 
of 
administration
IV
IV
IV
IV
IV
IV
External 
beam 
radiation
Dosing 
instructions:d
Saline 
volume 
matching 
durvalumab 
volume
Cisplatin 
on Days 
1 and 8
Etoposide 
cycles 
+1 additional
induction 
cycle
optional
Concurrent 
thoracic 
radiotherapy
Carboplatin AUC 2 and
Paclitaxel 
on 
- Concurrent thoracic
radiotherapy
Optional:paclitaxel 
 
mg/m2 and carboplatin 
 given either as 1 
induction 
cycle 
prior 
to 
initiation of radiotherapy OR
as 1-2  consolidation cycles 
after radiotherapy is completed
Pemetrexed 
and 
cisplatin 
on 
+1 additional
induction
cycle optional
Pemetrexed 
5 fractions/ 
week 
for 
(±3 days)
(Total 
60 Gy)
Packaging and 
labelling
Provided in 
 
vials, labelled in 
accordance 
with 
GMP Annex 13 
and per country 
regulatory -require
mentf
Sourced 
locally 
by 
site
Sourced locally by 
site
Sourced locally by site
Sourced 
locally by site
Sourced 
locally 
by 
site
Sourced 
locally 
by 
site
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Table 5
Study treatments
Durvalumab
Placebo
Standard of carea
Provider
AstraZeneca
Sourced 
locally by 
siteg
Sourced locally 
by siteg
Sourced locally by siteg
Sourced 
locally by siteg
Sourced 
locally by 
siteg
Sourced 
locally by 
site
Note: Cycles of durvalumab/placebo are 
 cycles of chemotherapy are per local prescribing guidelines.
a
Under certain circumstances when local sourcing is not feasible, an SoC treatment may be supplied centrally through AstraZeneca.
b
Patients with non-squamous NSCLC only. Administer vitamin B12 and folic acid as per pemetrexed prescribing instructions.
c
Refer to Section 6.2 for detailed formulation and preparation instructions for IPs.
d
Detailed instructions for IP administration are provided below. Refer to Section 6.1.1.1 for details on duration of treatment.
e
If a patient’s weight falls to 30 kg or below, the patient should receive weight-based dosing equivalent to 
 of durvalumab 
 until the weight
improves to >30 kg, at which point the patient should start receiving the 
 of durvalumab 
.
f
Label text will show the product name as “MEDI4736” or “durvalumab (MEDI4736)” depending upon the agreed product name used in the approved study 
master label document. All naming conventions are correct during this transitional period.
g
Under certain circumstances when local sourcing is not feasible, AstraZeneca will centrally source the drug, which will be labeled with text translated to 
local language in accordance with regulatory guidelines.
AUC Area under the curve; GMP Good Manufacturing Practice; IV Intravenous; NSCLC Non-small cell lung cancer; 
Every 
; 
SoC Standard of care.
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6.1.1.1
Durvalumab (MEDI4736) or placebo
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion. The solution contains 50 mg/mL durvalumab (MEDI4736), 
 histidine/histidine 
hydrochloride, 
 trehalose- dihydrate, and 
 weight/volume (w/v) polysorbate 80; it 
has a pH of 
 The nominal fill volume is 10.0 mL. Investigational product vials are stored at 
2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in secondary 
packaging until use to prevent excessive light exposure.
Saline solution will serve as the placebo in this study.
Durvalumab 
 or placebo will be administered 
 via IV infusion (see Table 5) 
concurrent with SoC CRT (ie, starting on Cycle 1 Day 1 [±3 days]). Patients with CR, PR, or SD 
(based on Investigator assessment) at the 16-week tumor evaluation following completion of 
SoC CRT will continue to receive durvalumab/placebo as consolidation treatment until 
RECIST 1.1-defined PD, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. Patients with RECIST 1.1-defined radiological PD will proceed 
to follow-up.
Crossover within the study will not be permitted.
If chemotherapy and/or radiation is discontinued due to treatment-related toxicity, treatment with 
durvalumab or placebo may continue at the Investigator’s discretion when toxicity resolves to 
Grade 2 or less. Note: if the Investigator feels a patient is ready to restart treatment prior to the 
toxicity resolving to Grade 2 or less, AstraZeneca/MedImmune should be consulted for an 
exception to this rule. Additional details for dosing delays can be found in Section 8.4.5. 
6.1.1.2
SoC CRT
SoC CRT agents will be supplied locally where possible. Patients will receive 1 of the SoC 
platinum-based chemotherapy options outlined in Table 5, based on Investigator discretion, in 
addition to radiation therapy (as described in Table 5). Concurrent radiation therapy will be 
administered according to the guidelines outlined in Appendix G. Treatment with SoC CRT will 
be concurrent with durvalumab/placebo (ie, starting on Cycle 1 Day 1 [±3 days]). In order to 
allow adequate time for coordination of radiation therapy, at the discretion of the treating 
physician, an additional planned “induction” cycle of certain chemotherapy regimens may be 
administered prior to the initiation of radiotherapy. If an optional induction chemotherapy cycle 
is administered prior to initiation of radiation therapy, durvalumab/placebo will begin on the 
same day as induction chemotherapy (Cycle 1 Day 1). For the paclitaxel/carboplatin regimen, 
investigators have the option of administering 1 induction cycle three weeks before initiating 
radiotherapy OR administering up to 2 consolidation cycles after completion of radiotherapy (but 
may NOT administer both induction and consolidation for this regimen). Specific dosing
information is detailed in Table 5.  
In the event that durvalumab/placebo is discontinued or temporarily held due to treatment-related 
toxicity, SoC CRT may still be administered as scheduled at the Investigator’s discretion.
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On days when both durvalumab/placebo and SoC CRT are administered, durvalumab/placebo 
will be administered first, followed by SoC chemotherapy.
6.1.1.3
Placebo 
The saline placebo solution will be administered using an IV bag that is identical in size to the 
durvalumab solution. A volume of normal saline equal to the volume of durvalumab as specified 
in Section 6.2 will be added to the IV bag.  The IV bag should be covered with an opaque sleeve 
after preparation by the unblinded pharmacist prior to dispensing to other study personnel to 
maintain double-blind conditions.
6.1.1.4 Post Final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure may continue to receive their assigned treatment for as long as they and their 
physician considers they are gaining clinical benefit. For patients continuing to receive 
durvalumab treatment following the final DCO and database closure, it is recommended that the 
patients continue the scheduled site visits and Investigators monitor the patients’ safety 
laboratory results prior to and periodically during treatment with durvalumab in order to manage 
AEs in accordance with the durvalumab Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1). 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab may be transitioned 
to such a study, and the current study would reach its end. The roll-over or safety extension study 
would ensure treatment continuation with visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new Informed Consent.
Investigators should continue to monitor and document data for all study patients in the database 
after scheduled DCO for final analysis of the global cohort and final database lock. Dependent 
on the analysis results of the global cohort, a decision may be made to continue further data 
collection for a longer period with intent to analyze long-term OS and safety data to fulfill any 
other potential Health Authority requirements. Any additional long-term analysis may be further 
clarified through addendum to main statistical analysis plan, which will be developed before 
DCO for the long-term analysis. Data will be collected until any of following conditions are met:
!
Until remaining patients in the study (including patients after discontinuation of study 
treatment) have discontinued the study OR
!
Remaining patients have been transferred to a roll-over study OR
!
If the sponsor decides to stop data collection, patients ongoing study treatment at this 
time and deriving clinical benefit from their assigned treatment will be allowed to 
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Patients moving to the roll over study will require a new informed consent. The OS data 
collected in the roll over study may be combined with the OS data from PACIFIC 2 and 
evaluated as a combined dataset. 
6.2
Preparation/handling/storage/accountability
6.2.1
Product preparation of durvalumab
The dose of durvalumab (MEDI4736) for administration must be prepared by the unblinded 
pharmacist using aseptic technique. Total time from needle puncture of the durvalumab 
(MEDI4736) vial to the start of administration should not exceed: 
!
!
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of 
administration.
6.2.2
Preparation of durvalumab doses for administration with an IV bag
A dose of 
 (for patients >30 kg in weight) will be administered using an IV bag 
containing 
, with a final durvalumab (MEDI4736) 
concentration ranging from 
, and delivered through an IV administration set with 
a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 
 mg of 
durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 
. Mix the bag by gently inverting to ensure homogeneity 
of the dose in the bag. The IV bag should be covered with an opaque sleeve after preparation by 
the unblinded pharmacist prior to dispensing to other study personnel to maintain double-blind 
conditions.
If weight falls to ≤30 kg, weight-based dosing at 
 will be administered using an IV bag 
containing 
 with a final durvalumab (MEDI4736) 
concentration ranging from 
, and delivered through an IV administration set with 
a 
 in-line filter.
The time from needle puncture of vial to start of administration should be up to 
. In the 
event that there are interruptions during infusion, the total allowed infusion time should not 
exceed 
 at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line 
was not flushed.
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If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any unused 
portion must be discarded.
6.2.3
Preparation of placebo for administration with an IV bag
The placebo solution will be identical in color to the durvalumab solution and will be 
administered using an IV bag that is identical in size to the durvalumab IV bag (see 
Section 6.2.2). A total of 30.0 mL normal saline will be added to the IV bag. Additional 
preparation and administration details will be identical to those for durvalumab (see 
Section 6.2.2).
6.2.4
Storage and accountability
The unblinded pharmacist must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved by supply chain before use of the study treatment.
The unblinded pharmacist will ensure that all IP is stored in a secured area, in refrigerated 
temperatures (2°C to 8°C for durvalumab and according to local guidelines for SoC) and in 
accordance with applicable regulatory requirements. A temperature log will be used to record the 
temperature of the storage area. Temperature excursions outside the permissible range listed in 
the clinical supply packaging are to be reported to the unblinded monitor upon detection. A 
calibrated temperature monitoring device will be used to record the temperature conditions in the 
drug storage facility. Durvalumab storage conditions stated in the IB may be superseded by the 
label storage.
The IP provided for this study will be used only as directed in the study protocol.
IPs will not be distributed to the study site until the contract is concluded between the study site 
and AstraZeneca. The unblinded pharmacist is responsible for managing the IPs from receipt by 
the study site until the return of all unused IP to AstraZeneca. AstraZeneca will provide the study 
documents “Procedures for drug accountability” and ‘Procedures for drug storage,” which 
describes the specific requirements. The Investigator(s) is responsible for ensuring that the 
patient has returned all unused IP.
6.3
Measures to minimize bias: randomization and blinding
All patients will be centrally assigned to randomized study treatment using an interactive 
voice/web response system (IVRS/IWRS). Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log-in information and directions for the IWRS 
will be provided to each site. 
Patients may be enrolled but not randomized. If a patient is not randomized, the IVRS/IWRS 
should be contacted to terminate the patient in the system.
If a patient withdraws from the study, then his/her enrolment/randomization code cannot be 
reused, and they cannot re-enter into the study. Withdrawn patients will not be replaced.

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The IVRS/IWRS will also be used to track drug supply.
6.3.1
Procedures for randomization
Patients must not be randomized unless all eligibility criteria have been met. 
Patients will be randomized in a 2:1 ratio to either durvalumab + SoC CRT or placebo + SoC 
CRT. Patients will be stratified by age 
) and stage (
The actual IP given to patients will be determined by the randomization scheme in the 
IVRS/IWRS. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. One randomization list 
will be produced for each of the randomization strata. A blocked randomization will be 
generated, and all centers will use the same list in order to minimize any imbalance in the 
number of patients assigned to each treatment arm.
Patients will be identified to the Centralized Randomization Center per country regulations. 
Randomization codes will be assigned 
, within each stratum, as patients 
become eligible for randomization. The IVRS/IWRS Centralised Randomization Centre will 
inform the unblinded pharmacist of the kit identification number to be allocated to the patient at 
the randomization visit.
Every effort should be made to minimize the time between randomization and starting study 
treatment. It is recommended that patients commence study treatment as soon as possible after 
randomization (ie, on the same day after randomization in the IVRS system).
The Investigator will call/log in to the IVRS/IWRS for each subsequent dispensing visit for 
assignment of a new kit identification number. The kit identification number dispensed at each 
visit will correspond to the IP to which the patient was originally randomized. 
If a patient discontinues participation in the study, then his/her enrolment/randomization code 
cannot be reused.
6.3.2
Methods for ensuring blinding
The study will be conducted in a double-blind manner. The diluted durvalumab and placebo (IV 
saline solution) will be blinded using an opaque sleeve, fastened with tamper-evident tape over 
the IV bag prior to dispensing to other study personnel to maintain the double-blind conditions. 
The patient, the Investigator, and study center staff will be blinded to the durvalumab/placebo 
allocation. The study center pharmacist will be unblinded to the durvalumab/placebo allocation 
and will prepare durvalumab or placebo for a patient as specified by the randomization scheme 
and IVRS (only the unblinded pharmacist will know the randomization/treatment allocation 
details). Pharmacists will be given specific instructions for durvalumab/placebo preparation and 
will note if the double-blind conditions have been compromised or the blind has been broken. 
Lot numbers of durvalumab dispensed will be recorded by the pharmacist and monitored by an 
unblinded monitor. Other study center staff and monitors will not be given access to lot number 
information. 
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No member of the extended study team at AstraZeneca/MedImmune, at the investigational 
centers, or any blinded contract research organization handling data will have access to the 
randomization scheme until the time of the final data analysis or any IA data where the study has 
met 1 of the primary endpoints and a decision is made to unblind the study at that timepoint. At 
such time, AstraZeneca/MedImmune and any Contract Research Organisation handling data will 
have access to the randomization scheme. Exceptions are relevant persons within the 
Pharmaceutical Development Supply Chain at AstraZeneca/MedImmune or their designee, 
where the information is needed to package the durvalumab/placebo; the drug safety departments 
at AstraZeneca/MedImmune; and the pharmacists required to dispense the durvalumab/placebo 
at the study site. Investigators will be unblinded to treatment allocation only in cases of medical 
emergency. Additionally, at the request of the Investigator, following discontinuation of IP and 
RECIST 1.1-defined progression of disease plus the additional regularly scheduled follow-up 
scan the patient can be unblinded. In the setting of rapid clinical progression, unblinding should 
be discussed with the AstraZeneca Global Study Physician and Study Statistician.
The IDMC will be provided with unblinded data for their review via a vendor independent of the 
rest of the study conduct, analysis, and reporting; AstraZeneca/MedImmune staff and 
Investigators involved in the study will remain blinded.
6.3.3
Methods for unblinding the study
Individual treatment codes, indicating the treatment randomization for each randomized patient, 
will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines for this 
will be described in the IVRS/IWRS user manual that will be provided to each center.
The treatment code should not be broken by the investigator except in medical emergencies 
when the appropriate management of the patient requires knowledge of the treatment 
randomization. Additionally, at the request of the Investigator, following discontinuation of IP 
and RECIST 1.1-defined progression of disease plus the additional regularly scheduled follow-
up scan the patient can be unblinded. The Investigator documents and reports the action to 
AstraZeneca, without revealing the treatment given to a patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected to 
be causally related to an IP and that potentially require expedited reporting to regulatory 
authorities. Treatment codes will not be broken for the planned analyses of data until all 
decisions on the evaluability of the data from each individual patient have been made and 
documented.
6.4  
Treatment compliance
The administration of all IPs should be recorded in the appropriate sections of the electronic case 
report form (eCRF).
Any change from the dosing schedule, does interruptions, dose reductions, and dose 
discontinuations should be recorded in the eCRF.
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The unblinded pharmacist is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. The Investigator(s) is responsible for ensuring that the 
patient has returned all unused IP.
6.5
Concomitant therapy
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical treatment phase of the study, including the follow-up 
period following the last dose of IP. Any concomitant medication(s), including herbal 
preparations, taken during this time will be recorded in the eCRF. 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer also to the Dosing Modification and Toxicity Management Guidelines in 
Section 8.4.5.1. For agents in the SoC CRT arm, please refer to the local prescribing information 
with regards to warnings, precautions, and contraindications. 
Table 6
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly while the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [eg, by local surgery or radiotherapy])
Live attenuated vaccines 
Should not be given through 
 after the last 
dose of IP
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Prohibited medication/class of drug:
Usage:
Immunosuppressive medications, including but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:
!
Use of immunosuppressive medications for 
the management of IP-related AEs, 
!
Short-term premedication for patients 
receiving SoC CRT, in which the prescribing 
information or local guidance for the agent 
requires the use of steroids for documented 
hypersensitivity reactions, nausea/vomiting, 
prophylaxis, etc.
!
Use in patients with contrast allergies. 
!
In addition, use of inhaled, topical, and 
intranasal corticosteroids are permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (eg, chronic 
obstructive pulmonary disease, radiation, nausea, 
etc.).
EGFR TKIs
Should not be given concomitantly 
Should be used with caution in the 
 post last 
dose of durvalumab.
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the sponsor
AE Adverse event; CRT Chemoradiation therapy; CTLA-4 cytotoxic T-lymphocyte antigen 4; EGFR Epidermal 
growth factor receptor; I-O Immuno-oncology; IP Investigational product; 
 
 SoC Standard of care; TKI Tyrosine kinase inhibitor.
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Table 7
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for 
those medications identified as “prohibited,” as 
listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management)
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
6.5.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
6.5.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-clinically 
or in patients. As durvalumab is a mAb and therefore a protein, it will be degraded to small 
peptides and amino acids and will be eliminated by renal and reticuloendothelial clearance. It is 
therefore not expected that durvalumab will induce or inhibit the major drug metabolizing 
cytochrome P450 pathways. As a result, there are no expected 
 drug-drug interactions. The 
mechanism of action of durvalumab involves binding to PD-L1, and therefore significant 
pharmacodynamic drug interactions with the commonly administered concomitant medications 
are not expected. Despite this, appropriate clinical monitoring in all of the planned clinical 
studies will be conducted to evaluate any potential drug-drug interactions.
6.5.3
Rescue medication
As a result of imAEs that could potentially be experienced by patients on durvalumab, 
immunosuppressant rescue medication has to be made available to this patient population. The 
2 products that fall into this category are infliximab (for colitis) and mycophenolate (for 
hepatitis). AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications 
to the sites if local regulations prevent the use of infliximab and mycophenolate in this 
indication, as they are considered off-label for management of immunotherapy related toxicities. 
These rescue medications must be receipted, controlled, and administered by the unblinded 
pharmacist and stored according to the labelled storage conditions, with temperature excursions 
reported accordingly by the unblinded pharmacist.  If required for use as a result of an immune-
mediated adverse event (imAE), then the interactive voice response system (IVRS)/interactive 
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web response system (IWRS) will provide to the unblinded pharmacists the kit identification 
number to be allocated to the patient at the time. Blinded and unblinded access and notifications 
will be controlled using the IVRS/IWRS.
6.6
Dose modification
Dose modifications are permitted in the management of certain IP-related toxicities as described 
in Section 8.4.5. In case a dose reduction is necessary, durvalumab/placebo will be administered 
as described in the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5.1). Modification of SoC CRT will be based on local prescribing and labelling 
guidelines.
6.7
Treatment after the end of the study
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab treatment up to the time that they discontinue the treatment for whatever 
reason (see Section 6.1).
7.
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL 
7.1
Discontinuation of study treatment
An individual patient will not receive any further IP (SoC CRT, durvalumab, or placebo) if any 
of the following occur in the patient in question:
!
Withdrawal of consent from further treatment with IP. The patient is, at any time, free 
to discontinue treatment, without prejudice to further treatment. A patient who 
discontinues treatment is normally expected to continue to participate in the study 
unless they specifically withdraw their consent to further participation in any study 
procedures and assessments (see Section 7.3). 
!
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing
!
Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5.1) or as defined in the local 
prescribing information for the SoC CRT agents
!
Pregnancy or intent to become pregnant
!
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits)
!
Initiation of alternative anticancer therapy including another investigational agent

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!
Clinical progression and Investigator determination that the patient is no longer 
benefiting from treatment with IP
!
RECIST 1.1-defined radiological PD
In the event that durvalumab/placebo is discontinued due to treatment-related toxicity, SoC CRT 
may still be administered as scheduled. If SoC CRT is discontinued due to treatment-related 
toxicity, durvalumab/placebo may continue at the Investigator’s discretion when toxicity 
resolves to Grade 2 or less. Note: if the Investigator feels that a patient is ready to restart 
treatment prior to the toxicity resolving to Grade 2 or less, AstraZeneca should be consulted for 
an exception to this rule.
7.1.1
Procedures for discontinuation of study treatment
At any time, patients are free to discontinue IP without prejudice to further treatment. A patient 
who decides to discontinue IP will always be asked about the reason(s) for discontinuation and 
the presence of any AE. If possible, they will be seen and assessed by an Investigator. AEs will 
be followed up (see Section 8.3). The Study Physician should be notified of any ongoing AE that 
may delay treatment or necessitate permanent discontinuation of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs). 
Patients who permanently discontinue study drug for reasons other than objective RECIST 1.1 
disease progression should continue to have RECIST 1.1 assessments performed 
 ±1 week 
beginning 
 after randomization for the first 
 (relative to the date of 
randomization), and then 
 ±1 week thereafter until RECIST 1.1-defined PD or death 
(whichever comes first) as defined in the SoAs.
If a patient is discontinued for RECIST 1.1-defined progression, then the patient should have 
1 additional follow-up scan performed preferably at the next (and no later than the next) 
scheduled imaging visit, and no less than 
 after the prior assessment of PD.
All patients will be followed for survival until the end of the study. 
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative. 
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
If a patient is withdrawn from study, see Section 7.3.
7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed (see Section 4.4), such that there is insufficient information to determine 
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the patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than “lost 
to follow-up.”  Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. Patients should be considered “potentially lost to 
follow-up” if contact is lost at any time during the study. If contact with a missing patient is 
re-established, the patient should not be considered potentially lost to follow-up, and evaluations 
should resume according to the protocol.
In order to support the key endpoints of PFS/OS, the survival status of all patients in the full 
analysis and the safety analysis sets should be re-checked; this includes those patients who 
withdrew consent or are classified as “potentially lost to follow-up.”
!
Potentially lost to follow-up – site personnel should check hospital records, the 
patients’ current physician, and a publicly available death registry (if available) to 
obtain a current survival status. (The applicable eCRF modules will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable eCRF 
modules will be updated.)
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.
!
Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by, for example, repeat 
telephone calls, certified letter to the patient’s last known mailing address, or local 
equivalent methods. These contact attempts should be documented in the patient’s 
medical record. 
!
Efforts to reach the patient should continue until the end of the study. Should the 
patient be unreachable at the end of the study, the patient should be considered to be 
lost to follow-up with unknown vital status at the end of study and censored at latest 
follow-up contact.
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice 
to further treatment.
Patients who withdraw consent for further participation in the study will not receive any further 
IP or further study observation, with the exception of follow-up for survival, which will continue 
until the end of the study unless the patient has expressly withdrawn their consent to survival

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follow-up. Note that the patient may be offered additional tests or tapering of treatment to 
withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to:
!
all further participation in the study including any further follow-up (eg, survival contact 
telephone calls)
!
withdrawal to the use of any samples (see Appendix C)
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The Investigator will ensure that data are recorded on the eCRF as specified in the 
study protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes, provided 
that the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA.
8.1
Efficacy assessments
This study will evaluate the primary endpoint of PFS. The key secondary endpoints (ie, those 
included in the multiple testing procedure) are ORR, OS and OS24. Efficacy assessments of 
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assessments according to RECIST 1.1. A sensitivity analysis of PFS will be performed using 
Investigator assessments.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV contrast, 
of the chest and abdomen (including the entire liver and both adrenal glands), collected during 
screening/baseline and at regular (follow-up) intervals during study treatment. Any other areas of 
disease involvement should be additionally imaged based on the signs and symptoms of 
individual patients. It is important to follow the tumor assessment schedule as closely as possible 
(refer to the SoAs). If an unscheduled assessment is performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at the next 
scheduled visit. Treatment continues until clinical progression/deterioration or radiological 
progression by RECIST 1.1, and scanning/tumor assessments continue throughout treatment 
until RECIST 1.1-defined radiological progression plus an additional follow-up scan (if 
clinically feasible).
The RECIST 1.1 guidelines (0) provide a method of assessment of change in tumor burden in 
response to treatment. Screening/Baseline imaging should be performed no more than 28 days 
before the date of randomization, and ideally should be performed as close as possible to and 
prior to the date of randomization. The RECIST 1.1 assessments of baseline images identify TLs 
(defined as measurable) and Non-Target Lesions (NTLs). On-study images are evaluated for TLs 
and NTLs chosen at baseline, and for New Lesions (NLs) when they appear. This allows 
determination of follow-up TL response, NTL lesion response, the presence of unequivocal NLs, 
and overall timepoint responses (CR, PR, SD, PD, or Not Evaluable [NE]).
8.1.1
Central reading of scans
All images, including unscheduled visit scans, will be collected on an ongoing basis and sent to 
an AstraZeneca-appointed Contract Research Organization for QC and storage. Guidelines for 
image acquisition, de-identification, storage at the investigative site as source data, and transfer 
to the imaging CRO will be provided in a separate document. A BICR of images will be 
performed at the discretion of AstraZeneca. Results of these independent reviews will not be 
communicated to Investigators and results of Investigator RECIST 1.1 assessments will not be 
shared with the central reviewers. The management of patients will be based in part upon the 
results of the RECIST 1.1 assessment conducted by the Investigator. Further details of the BICR 
will be documented in the Independent Review Charter, (also referred to as ‘Imaging Charter’).
8.1.2
Survival assessments
Assessments for survival must be made 
 (±2 weeks) following treatment discontinuation. 
Survival information may be obtained via telephone contact with the patient or the patient’s 
family or by contact with the patient’s current physician. The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected. 
In addition, patients on treatment or in survival follow-up will be contacted following the DCO 
for the primary analysis and all subsequent survival analyses to provide complete survival data. 
These contacts should generally occur within 7 days of the DCO.
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8.1.3
Clinical outcome assessments
PRO is an umbrella term referring to all outcomes and symptoms that are directly reported by the 
patient. PROs have become a significant endpoint when evaluating effectiveness of treatments in 
clinical studies. The following PROs will be administered in this study: EORTC QLQ-C30 v3 
(core questionnaire), EORTC QLQ-LC13 (lung cancer module), PGIS and 5-level health state 
utility index (EQ-5D-5L) (see Appendix H).
8.1.3.1
EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists of 
30 items and measures cancer patients’ symptoms, functioning, and health-related quality of life 
(HRQoL) (Aaronson et al 1993) for all cancer types. Questions are grouped into 5 multi-item 
functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom scales 
(fatigue, pain, nausea, and vomiting); a 2-item global HRQoL scale; 5 single items assessing 
additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, 
constipation, and diarrhea), and 1 item on the financial impact of the disease. The EORTC 
QLQ-C30 is a valid and reliable PRO instrument in this patient population.
The QLQ-LC13 is a well-validated complementary module measuring lung cancer associated 
symptoms and side effects from conventional chemotherapy and radiotherapy (Bergman et al 
1994). The QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site specific 
pain (symptoms), sore mouth, dysphagia, peripheral neuropathy, alopecia (treatment-related side 
effects), and pain medication.
8.1.3.2
PGIS
The Patient Global Impression of Severity (PGIS) item is included to assess how a patient 
perceives his/her overall current severity of cancer symptoms. Patients will choose from 
response options from “No symptoms” to “Very severe.”
8.1.3.3EQ-5D-5L
The EuroQoL 5-Dimension (EQ-5D) is a standardized measure of health status developed by the 
EuroQol Group in order to provide a simple, generic measure of health for clinical and economic 
appraisal (EuroQoL Group 1990). Applicable to a wide range of health conditions and 
treatments, it provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as in population health 
surveys. The questionnaire assesses 5 dimensions as follows: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 response options (“no problems,” 
“slight problems,” “moderate problems,” “severe problems,” and “extreme problems”) that 
reflect increasing levels of difficulty (EuroQoL Group 2013).
Since 2009, the EuroQol Group has been developing a more sensitive version of the EQ-5D (the 
EQ-5D-5L) that expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011). Preliminary studies indicate that the 5L version 
improves upon the properties of the 3L measure in terms of reduced ceiling effect, increased 
reliability, and an improved ability to differentiate between different levels of health (Janssen et 
al 2008a, Janssen et al 2008b, Pickard et al 2007).

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The patient will be asked to indicate his/her current health state by selecting the most appropriate 
level in each of the 5 dimensions. The questionnaire also includes a visual analog scale, where 
the patient will be asked to rate current health status on a scale of 0 to 100, with 0 being the 
worst imaginable health state (see Appendix H). 
8.1.3.4
Administration of patient-reported outcomes questionnaires
Patients will perform the PRO assessments using an electronic tablet (ePRO) during clinic visits 
and will take approximately 10 minutes to complete.
Each center must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a back-up 
person to cover if that individual is absent. The PRO questionnaires must be administered and 
completed at the clinic as per the SoAs. 
It is important that the site staff explains the value and relevance of PRO data: to hear directly 
from patients how they feel. The following best practice guidelines should be followed:
!
It is preferred that PRO questionnaires are completed prior to any other study 
procedures (following informed consent) and before discussion of disease progression 
to avoid biasing the patient’s responses to the questions.
!
PRO questionnaires must be completed in private by the patient.
!
Patient should be given sufficient time to complete the PRO questionnaires at their 
own speed.
!
The research nurse or appointed site staff should stress that the information is 
confidential. Therefore, if the patient has any medical problems, he or she should 
discuss them with the doctor or research nurse separately from the ePRO assessment.
!
The research nurse or appointed site staff must train the patient on how to use the 
 using the materials and training provided in the 
. 
!
The research nurse or appointed site staff must remind patients that there are no right 
or wrong answers and avoid introducing bias by not clarifying items. The patient 
should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. 
A key aspect of study success is to have high PRO compliance. Therefore it is essential to follow 
SoA and that sites make sure the device is charged and fully functional at all times in order to 
minimize missing data.
8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
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8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the times indicated in the assessment schedules and as clinically indicated (see the 
SoAs). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Urine pregnancy 
tests may be performed at the site using a licensed test (urine or serum pregnancy test). 
Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will be 
recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 8 (clinical chemistry), Table 9
(hematology), and Table 10 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.
The following laboratory variables will be measured:

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Table 8
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSHd
Chloridec
T3 freee (reflex)
Creatininec
T4 freee (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If 
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into 
direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters 
is routinely measured, then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine, gamma glutamyltransferase, and magnesium testing are to 
be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry assessments are 
performed within 3 days prior to Day 1), and if clinically indicated.
d
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
e
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system
ALT Alanine aminotransferase; AST Aspartate aminotransferase, T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid 
Stimulating Hormone.
Table 9
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed at 
baseline on Day 1 of cycle 1 (unless all screening laboratory hematology assessments are performed within 3 days prior to 
Day 1), and as clinically indicated.
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data Management 
if entered as percentage. Total white cell count, therefore, has to be provided.

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Table 10
Urinalysis
Urinalysis should be done at baseline (screening) and then as clinically indicated
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood cells. 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a 
Hy’s law case or if any of the individual liver test parameters fulfill any of the SAE criteria. 
All patients should have further chemistry profiles performed at 
 (±3 days), 
 
(±1 week) and 
 (±1 week) after permanent discontinuation of IP (see SoAs).
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 or 
2, unless these values are not likely to improve because of the underlying disease.
8.2.2
Physical examinations
Physical examinations will be performed according to the assessment schedules (see SoAs). Full 
physical examinations will include assessments of the head, eyes, ears, nose, and throat and the 
respiratory, cardiovascular, gastrointestinal (GI), urogenital, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at 
screening only. Targeted physical examinations are to be utilized by the Investigator on the basis 
of clinical observations and symptomatology. Situations in which physical examination results 
should be reported as AEs are described in Section 8.3.6. 
8.2.3
Electrocardiograms
Resting 12-lead electrocardiograms (ECGs) will be recorded at screening and as clinically 
indicated throughout the study (see the SoAs). ECGs should be obtained after the patient has 
been in a supine position for 5 minutes and recorded while the patient remains in that position. 
In case of clinically significant ECG abnormalities, including a QT interval corrected for heart 
rate using Fridericia’s formula (QTcF) value >470 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (eg, 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
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8.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiratory rate) will be evaluated 
according to the assessment schedules (see the SoAs). Body weight is also recorded at each visit 
along with vital signs. The following timepoints for vital signs assessments apply to infusions of 
durvalumab/placebo. Vital signs assessments related to SoC CRT administration should be 
performed according to local clinical practice.
First infusion
On the first infusion day, patients will be monitored and vital signs will be collected/recorded in 
the eCRF prior to, during, and after infusion of IP as presented in the bulleted list below. 
BP and pulse will be collected before, during, and after each durvalumab/placebo infusion at the 
following times (based on a 60-minute infusion):
!
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minute [ie, the beginning of the infusion])
!
Approximately 30 minutes during the infusion (halfway through infusion) 
!
At the end of the infusion ( approximately 60 minutes ±5 minutes)
!
A 
 period is recommended after the first infusion of 
durvalumab/placebo. If no clinically significant infusion reactions are observed during 
or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (
 after each durvalumab/placebo 
infusion). 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated. Additional 
monitoring with assessment of vital signs will be at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.
Subsequent infusions
BP, pulse, and other vital signs should be measured and collected/recorded in eCRF prior to the 
start of the infusion. Patients should be carefully monitored and BP and other vital signs should 
be measured during and post infusion as per institution standard and as clinically indicated. Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
eCRF page. 
Situations in which vital signs results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, please enter the vital signs values into the eCRF.
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8.2.5
WHO/ECOG performance status
WHO/ECOG PS will be assessed at the times specified in the SoA based on the following:
0.
Fully active; able to carry out all usual activities without restrictions
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (eg, light housework or office work)
2.
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours
3.
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4.
Completely disabled, unable to carry out any self-care and totally confined to bed or 
chair
Any significant change from baseline or screening must be reported as an AE.
8.2.6
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5.1) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography (HRCT), 
blood and sputum culture, hematological parameters, etc.) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis /ILD should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed. 
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
(including images) will be collected.
!
Physical examination
∀
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed.
!
SpO2
∀
Saturation of peripheral oxygen (SpO2)

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!
Other items
∀
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers that are related to disease 
progression. 
(iii)
Additional Clinical chemistry: C reactive protein (CRP), lactate 
dehydrogenase (LDH) 
Brain MRI/CT
At screening, a brain MRI (preferred) or high-quality brain CT with IV contrast will be 
performed.
8.3
Collection of adverse events
The Investigator is responsible for ensuring that all staff involved in the study are familiar with 
the content of this section
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, see 
Section 8.3.3. 
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.2
Time period and frequency for collecting AE and SAE information 
AEs and SAEs will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (90 days after the last dose of IP).
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix B. The Investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 

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he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation or study completion.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
The maximum CTCAE grade reported
!
Changes in CTCAE grade
!
Whether the AE is serious or not
!
Investigator causality rating against the IPs (yes or no)
!
Action taken with regard to IPs
!
Administration of treatment for the AE
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date the AE met criteria for SAE
!
Date the Investigator became aware of the SAE
!
Seriousness criteria fulfilled
!
Date of hospitalization

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!
Date of discharge
!
Probable cause of death
!
Date of death
!
Whether an autopsy was performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication, as explained in Section 8.3.5
!
Description of the SAE
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 4.03 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria in Appendix B, B 2. An AE of severe intensity 
need not necessarily be considered serious. For example, nausea that persists for several hours 
may be considered severe nausea, but not an SAE unless it meets the criteria shown in 
Appendix B, B 2. On the other hand, a stroke that results in only a limited degree of disability 
may be considered a mild stroke, but it would be an SAE if it satisfies the criteria shown in 
Appendix B, B 2.
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship is 
implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study site staff, “Have you had any health problems since the previous visit/you were last 
asked?”, or revealed by observation will be collected and recorded in the eCRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 

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generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse events based on examinations and tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with an IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting Investigator uses 
the clinical, rather than the laboratory term (eg, anemia vs low hemoglobin value). In the absence 
of clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not be 
reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE.
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix E for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new or 
progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events that are unequivocally due to disease progression 
should not be reported as an AE during the study.
8.3.10
New cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after the 
patient’s inclusion in this study. 

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8.3.11
Deaths
All deaths that occur during the study treatment period or within the protocol-defined follow-up 
period after the administration of the last dose of IP must be reported as follows:
!
Death clearly the result of disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF 
in the Statement of Death page. It should not be reported as an SAE. 
!
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the Statement of Death page in the 
eCRF. The report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
post-mortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes. 
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of IP should be documented in the Statement of Death page. If the death occurred as 
a result of an event that started post the defined safety follow-up period and the event is 
considered to be due to a late onset toxicity to the IP then it should also be reported as an SAE.
8.3.12
Adverse events of special interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and rapid communication by the Investigator to the sponsor. An AESI 
may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterize and understand them in association with the use of this IP.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An imAE is defined as an AESI that is associated with drug exposure and 
is consistent with an immune-mediated mechanism of action and where there is no clear alternate 
etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions with regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician. AESIs may have additional clinical information 
collected in the eCRF.

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AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, myocarditis,myositis/polymyositis, pancreatitis and rare/less frequent imAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, and rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab IB. More specific guidelines for their evaluation and treatment are described 
in detail in the Dosing Modification and Toxicity Management Guidelines (please see 
Section 8.4.5.1). These guidelines have been prepared by the Sponsor to assist the Investigator in 
the exercise of his/her clinical judgment in treating these types of toxicities. These guidelines 
apply to AEs considered causally related to the IP/study regimen by the reporting investigator.
8.3.13
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1). All data post the final DCO and database closure 
will be recorded in the patient notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure must 
be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP or to the study 
procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he/she becomes aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel reports 
an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to proceed. 
The Principal Investigator is responsible for ensuring that procedures and expertise are available 
to handle medical emergencies during the study. A medical emergency usually constitutes an 
SAE and is to be reported as such.
For further guidance on the definition of an SAE, see Appendix B of the Clinical Study Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for 
pregnancy discovered before the study patient has received any IPs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or 
birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from 
the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but no later 
than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.

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The same timelines apply when outcome information is available.
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
 following the last dose of IP. Please follow the local prescribing information relating to 
contraception and the time limit for such precautions for SoC CRT agents.
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 
 after the last dose 
of IP should, if possible, be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner. Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.
8.4.3
Overdose
Use of durvalumab in doses in excess of that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of durvalumab, and 
possible symptoms of overdose are not established.
!
An overdose with associated AEs will be recorded as the AE diagnosis or symptoms in 
the relevant AE modules of the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms will only be reported in the Overdose 
eCRF module.
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately or no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 8.4.1. 
For other overdoses, reporting must occur within 30 days.
Refer to the local prescribing information for treatment of cases of overdose for any SoC CRT 
agents. If any overdose is associated with an AE or SAE, please record the AE/SAE diagnosis or 
symptoms in the relevant AE modules only of the eCRF.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but 
no later than 24 hours) of when he or she becomes aware of it.
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The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 or 5 calendar days if there is an SAE associated with the 
medication error (see Section 8.3.2) and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B.
8.4.5
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities:
!
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of the assigned IP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted.
!
All dose modifications should be documented with clear reasoning and documentation 
of the approach taken.
!
Patients should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression, concomitant medications, or infections). This includes SoC 
CRT-induced toxicity. 
!
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related, and the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1) should be followed.
!
In the event that durvalumab/placebo is discontinued or delayed as part of the Dosing 
Modification and Toxicity Management Guidelines, SoC CRT may still be 
administered as scheduled.
!
In the event that SoC CRT is discontinued due to treatment-related toxicity, 
durvalumab/placebo may continue at the Investigators discretion when toxicity 
resolves to at least Grade 2 or less. Note: if the Investigator feels that a patient is ready 
to restart treatment prior to the toxicity resolving to Grade 2 or less, AstraZeneca 
should be consulted for an exception to this rule.
If unsure how to manage a patient, please contact the Study Physician at AstraZeneca to discuss 
individual cases. All toxicities will be graded according to CTCAE version 4.03. 
8.4.5.1
Durvalumab
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in the Dosing Modification and 
Toxicity Management Guidelines. The most current version of these guidelines is also 
maintained within the Site Master File. In addition, a version of the current Dosing Modification 
and Toxicity Management Guidelines is available through the following link: 

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https://tmg.azirae.com. Please contact the clinical study associate for information on how to gain 
access to this website.
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related.
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 and the Dosing Modification and Toxicity Management 
Guidelines).  
Following the first dose of IP, the timing of subsequent administration of durvalumab can be 
modified based on toxicities observed as described in the Dosing Modification and Toxicity 
Management Guidelines (ie, dose delays). These guidelines have been prepared by the sponsor to 
assist the Investigator in the exercise of his or her clinical judgment in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to durvalumab by the 
reporting Investigator.
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician.
8.4.5.2
Standard of care agents
Chemotherapies are associated with a number of unwanted effects. SoC CRT-related toxicity 
management and dose adjustment, including dose delays and reductions, should be performed as 
indicated in the local prescribing information for the relevant agent. In the event of unfavorable 
tolerability, patients can switch between the permitted chemotherapy options at any point on 
study (assuming eligibility for the switched therapy is met).
In the event that an AE can reasonably be attributed to SoC CRT, dose adjustment of SoC CRT 
should be attempted before modifying the administration of durvalumab/placebo.
Every effort should be made to ensure patients receive all scheduled cycles of SoC CRT across 
all treatment arms in the study, if conditions allow.
8.5
8.5.1
Collection of samples
Blood samples for determination of 
 will be obtained 
according to the assessment schedules (see the SoAs). 
Samples for determination of 
 will be analyzed by a 
designated third party on behalf of AstraZeneca. Samples will be collected, labeled, stored, and 
shipped as detailed in the Laboratory Manual. Full details of the analytical method used will be 
described in a separate 
 Validation Report.
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8.5.2
Collection of samples to measure for the presence of 
The presence of 
 will be assessed in serum samples taken according to the assessment 
schedules (see the SoAs). 
Samples will be measured for the presence of 
 and 
 for 
durvalumab using validated assays. Tiered analyses 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 employed.  Samples will analyzed in an 
AstraZeneca-designated laboratory; additional details are provided in the Laboratory Manual.
8.5.3
Storage and destruction of 
 samples
 samples will be disposed of a maximum of 15 years from the end of the study.
 samples may be disposed of or destroyed and anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled 
 samples to further evaluate and 
validate the analytical method. Results from such analyses may be reported separately from the 
Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples. The results from the evaluation will not be reported in the CSR but separately in 
a Bioanalytical Validation Report.
Any 
 samples may be used for 
 (in this 
case, 
 samples will be shipped to the AstraZeneca-assigned 
 see 
details in the Laboratory Manual).
8.6
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study
8.7
8.7.1
Optional 
 sample
A 
 sample for 
 isolation will be collected from patients who have consented to 
participate in the 
 analysis component of the study. Participation is optional. Patients who 
do not wish to participate in the 
 research may still participate in the study. The 
 
 for 
 research will be obtained from the patients prior to 
 
In the event of 
 failure, a replacement 
 sample may be requested 
from the patient. Signed informed consent will be required to obtain a replacement sample unless 
it was included in the original consent.
See Appendix D for information regarding 
 research. Details on processes for collection 
and shipment and destruction of these samples can be found in Appendix D or in the Laboratory 
Manual.
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8.8
Biomarkers
By participating in this study, the patient consents to the mandatory collection and use of donated 
biological samples as described here. Blood and tissue samples will be obtained from all 
screened patients.
Based on availability of tissue, exploratory biomarkers may be evaluated as described in 
Section 8.8.1. Also, descriptions of exploratory, peripheral measures are described in this 
section. Samples will be obtained according to the assessment schedules provided in the SoAs.
Tumor biopsy samples should be formalin fixed and embedded in paraffin.
!
Samples should be collected via a core needle (
) or be collected as 
an excisional or incisional tumor biopsy sample.
!
Two cores should be placed in formalin and processed to a single paraffin-embedded 
block, as described in the Laboratory Manual.
!
The tumor specimen should be of sufficient quantity to allow for 
immunohistochemistry analyses (see the Laboratory Manual). Tumor tissue block is 
preferred. If a tissue block is unavailable, unstained sections from the tissue block may 
be submitted. Please consult the Laboratory Manual for specific instructions and 
guidelines regarding sections. Specimens with limited tumor content and fine-needle 
aspirates are inadequate.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
 as described in the exploratory 
analyses section.
The results may be pooled with biomarker data from other 
 studies to 
 and to 
 in 
 versus 
 settings.
Additional information regarding the handling of human biological samples is provided in 
Appendix C.
8.8.1
Exploratory biomarkers
Baseline measures will be 
. Note that samples will be obtained from 
patients randomized to each treatment arm. Comparisons will be made between baseline 
measures to determine if 
 
 associated with durvalumab + SoC CRT versus placebo + SoC CRT. 
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Additional sample collections and analyses may be completed at select study sites by 
site-specific amendment. All samples collected for such exploratory analyses will be stored at the 
study site, a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The exploratory biomarker plan is described by sample type below.
Soluble factors - plasma
Plasma will be obtained from all patients as described in the SoAs. The concentrations of a panel 
of relevant 
 may be assessed. Plasma may also be used to evaluate 
mutant 
. Correlations with outcome data may be completed on select 
candidates and predictive markers with the aim of identifying useful, appropriate cutoffs for 
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identifying patients likely to receive benefit, or alternatively, for identifying patients likely to 
suffer drug-related AEs.
Tumor markers
Tissue obtained as part of screening procedures will be analyzed for additional markers by 
immunohistochemistry. A primary goal is to measure 
 protein expression in 
an effort to 
. Based on availability of tissue, a panel 
of additional, immune-relevant markers expressed on tumor-infiltrating lymphocytes or on 
 
may be assessed. Markers of special interest include, but are not limited to, 
 
.
Tumor tissue may also be utilized to evaluate other relevant biomarkers, potentially including but
not limited to, somatic mutation detection methods for markers, such as tumor mutational 
burden, and gene expression methodologies to evaluate inflammatory signatures, potentially 
including but not limited to, 
.
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study investigator, general physician, or any other third party, unless required 
to do so by law. The patient’s samples will not be used for any purposes other than those 
described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
8.8.2
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 
 from the end of study, after which they will 
be destroyed. Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the CSR in a separate report. The results of 
this biomarker research may be pooled with biomarker data from other studies involving 
durvalumab to generate hypotheses to be tested in future research.
8.8.3
Labeling and shipment of biological samples
The Principal Investigator will ensure that samples are labeled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix C, C 3 “IATA 6.2 Guidance Document.”
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.
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8.9
Health economics
For the purposes of economic evaluation, it is necessary to capture health care resource use 
related to the treatment and the underlying disease. Within the study, the following will be 
captured:
!
Hospital episodes including the type of contact (hospitalizations, outpatient, or day 
case), reason, length of stay by ward type (including intensive care unit), and 
concomitant medications and procedures
!
Treatment related to AEs (including the method of delivery of the treatment)
!
Treatment not related to the study
The above resource use data will mainly come from the patient’s medical record and will be 
captured in the eCRF.
The assessment of health economic resource use data will provide important information for 
payers and will be used within economic evaluations of durvalumab.
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The formal statistical analyses will be performed to test the main hypothesis:
!
H0: No difference between durvalumab + SoC CRT and placebo + SoC CRT 
!
H1: Difference between durvalumab + SoC CRT and placebo + SoC CRT 
The primary objective of this study is to assess the efficacy of durvalumab + SoC CRT compared 
with placebo + SoC CRT in terms of PFS (per RECIST 1.1 as assessed by BICR). The key 
secondary endpoints (ie, those included in the multiple testing procedure) are ORR (per RECIST 
1.1 as assessed by BICR), OS, and OS24.
The study will be considered positive (a success) if the PFS analysis results are statistically 
significant. 
9.2
Sample size determination
The study will plan to enroll approximately 
 patients in order to randomize 300 eligible 
patients 2:1 to durvalumab + SoC CRT or placebo + SoC CRT. The randomization will be 
stratified by age 
) and stage 
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The study is powered for the primary endpoint (PFS) and for the key secondary endpoints of 
ORR and OS. Details of the sample size calculations are shown below. For the multiple testing 
procedure, refer to Section 9.4.8, and for details of the  alpha spending, refer to Section 9.5.
There are up to 
 will occur when approximately 
 of 
 PFS events (information fraction of 
 have occurred. It is estimated that this DCO will 
occur 
 after the last patient has been randomized. If the 
 is not positive, 
the DCO for the 
 will occur when approximately 
 events have 
occurred. It is estimated that this DCO will occur 
 after the last patient has been 
randomized. 
If the true PFS HR is 
 the study will provide greater than 
power to demonstrate a 
statistically significant PFS effect with a 2-sided significance level of 5%; this translates to a 
 benefit in median PFS over 
 on placebo if PFS 
. The 
smallest treatment effect that would be statistically significant is an HR of 
 at final analysis. 
There are up to 
 will occur at the 
 of the 
 if the 
. If the 
, the 
 will 
occur when approximately 
 (information fraction of 
 are reached. If the 
, then the 
 will occur when 
approximately 
 (information fraction of 
 are reached. Similarly, if 
, then the DCO for the 
 analysis will 
occur when approximately 
 events are reached.
If the true OS HR is 
 the study will have greater than 
 overall power to demonstrate a 
statistically significant OS effect with a 5% 2-sided significance level; this translates to a 
 if OS is 
. 
The smallest treatment difference that would be statistically significant is a HR of 
 at final 
analysis.
The study has 
 power to detect a statistically significant difference in 
 with a 2-
sided significance level of 
. This assumes the ORR for the patients randomized to placebo + 
SoC CRT is 
. The smallest treatment effect that would be statistically significant is a 
difference in ORR of 
.
9.3
Populations for analyses
Definitions of the analysis sets for each outcome variable are provided in Table 11.
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Table 11
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy Data
PFS
FAS (ITT population)
ORR, OS, OS24, CR rate, DoR, DCR at 
, PRO endpoints, 
and TTDM
FAS (ITT population)
Demography
FAS (ITT population)
PK data
PK analysis set
Safety Data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital Signs
Safety analysis set
ADA
ADA analysis set
ADA  Anti-drug antibody; CR Complete response; DCR Disease control rate; DoR  Duration of response; 
FAS Full analysis set; ITT  Intent-to-Treat; ORR  Objective response rate; OS Overall survival; PFS  Progression-
free survival; 
; PK  Pharmacokinetic; PRO  Patient-reported 
outcomes; TTDM  Time to death or distant metastasis
9.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients. The FAS will be used for all 
efficacy analyses (including PROs). Treatment arms will be compared on the basis of 
randomized study treatment, regardless of the treatment actually received. Patients who were 
randomized but did not subsequently go on to receive study treatment will be included in the 
analysis in the treatment arm to which they were randomized.
9.3.2
Safety analysis set
The safety analysis set will consist of all patients who received at least 1 dose of randomized 
treatment (durvalumab or matching placebo). Safety data will be summarized using the safety 
analysis set according to treatment received, that is, erroneously treated patients (eg, those 
randomized to treatment A but actually given treatment B) will be summarized according to the 
treatment they actually received.
9.3.3
All patients who receive at least 1 dose of durvalumab or placebo per the protocol, for whom any 
post-dose data are available and do not violate or deviate from the protocol in ways that would 
significantly affect the 
 analyses, will be included in the 
 analysis set. All patients who 
have non-missing baseline 
 and at least 1 non-missing post-baseline 
 result will be 
included in the 
 analysis set. The population will be defined by the study team physician, 
 and statistician prior to any analyses being performed.
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9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will be 
developed and finalized before database lock and will describe the patient populations to be 
included in the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. Any deviations from this plan will be reported in the CSR.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm. Continuous variables will be summarized by the number of observations, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be summarized 
by frequency counts and percentages for each category. Unless otherwise stated, percentages will 
be calculated out of the population total for the corresponding treatment arm.
Baseline will be the last assessment of the variable under consideration prior to the intake of the 
first infusion of IP, except for efficacy variables. For efficacy variables, baseline is defined as the 
last visit prior to randomization.
Efficacy and PRO data will be summarized and analyzed based on the FAS. 
 data will be 
summarized and analyzed based on the 
 analysis set. Safety data will be summarized using the 
safety analysis set.
Results of all statistical analyses will be presented using a 95% CI and p-value, unless otherwise 
stated.
9.4.1
Outcome measures for analysis
9.4.1.1
Calculation or derivation of efficacy variables
The analysis of PFS, ORR, rate of CR, DoR, DCR, and TTDM will be based on BICR tumor 
assessments according to RECIST 1.1. OS will be evaluated from all-cause mortality. 
Additionally, 
 will be defined by local standard clinical practice.
A 
 of PFS and ORR will be performed using the Investigator tumor 
assessments. 
RECIST 1.1 based endpoints
Blinded Independent Central Review of RECIST 1.1-based assessments
The BICR of radiological images (including those at unscheduled visits or outside visit 
windows) will be carried out using RECIST 1.1. The images will be reviewed by 2 independent 
radiologists using RECIST 1.1 criteria. For each patient, the BICR will define the overall visit 
response data (CR, PR, SD, PD, or NE) and the relevant scan dates for each timepoint (ie, for 
visits where response or progression is/is not identified). If a patient has had a tumor assessment 
that cannot be evaluated, then the patient will be assigned a visit response of NE (unless there is 
evidence of progression, in which case the response will be assigned as PD). If any of the overall 
visit responses (CR, PR, SD, PD, or NE) differ between the 2 primary radiologists, the case will 
be adjudicated by a third independent radiologist who will choose all assessments of the primary 
reviewer with which they agree more. If no differences in overall visit responses are identified, 
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then the assessments from the primary radiologist who completed their review of baseline scans 
first will be used for the analysis. Endpoints (of PFS, ORR, rate of CR, DoR, DCR, and TTDM) 
will be derived from the overall visit responses.
Further details of the BICR will be documented in the Independent Review (Imaging) Charter. 
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues IP or receives another 
anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, 
SD, or PD, depending on the status of their disease compared with baseline and previous 
assessments. Baseline will be assessed within the 
 prior to randomization. If a patient has 
had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE, unless there is evidence of progression, in which case the response will be 
assigned as PD. 
Please refer to 0 for the definitions of CR, PR, no evidence of disease (NED), NE, SD, and PD. 
Progression-free survival
PFS (per RECIST 1.1 as assessed by the BICR) will be 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 therapy or receives 
another anticancer therapy prior to progression (ie, date of event or censoring – date of 
randomization + 1). Patients who have not progressed or died at the time of analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment. However, if the patient progresses or dies after 2 or more missed visits, the patient 
will be censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed
visits. If the patient has no evaluable visits or does not have baseline data, he or she will be 
censored at Day 1 unless he or she dies within 2 visits of baseline, then they will be treated as an 
event with date of death as the event date. 
The PFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:
!
For BICR assessments, the date of progression will be determined based on the earliest 
scan dates of the component that triggered the progression for the adjudicated reviewer 
selecting PD or of the reviewer who read baseline first if there is no adjudication.
!
For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST 1.1 assessment/scan dates of the component that indicates 
progression.
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!
When censoring a patient for PFS, the patient will be censored at the latest of the scan 
dates contributing to a particular overall visit assessment.
Note: For TLs, only the latest scan date within an imaging visit window is recorded in the 
RECIST 1.1 eCRF out of all scans performed at that assessment for the TLs, and similarly for 
NTLs, only the latest scan date is recorded out of all scans performed at that assessment for the 
NTLs.
A sensitivity analysis of PFS will be performed using Investigator assessments according to 
RECIST 1.1.
Objective response rate
ORR (per RECIST 1.1 as assessed by BICR) is defined as the number (%) of patients with a 
confirmed response of CR or PR. 
A confirmed response of CR or PR means that a response of CR or PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 
 after the visit when the response was first 
observed, with no evidence of progression between the initial and CR/PR confirmation visit. 
Therefore, data obtained up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR. Patients who go off treatment without 
progression, receive a subsequent therapy, and then respond will not be included as responders in 
the ORR.
ORR will also be obtained using the algorithm described above for the RECIST 1.1 site 
Investigator tumor data.  
Overall survival
OS is defined as the time from the date of randomization until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last recorded 
date on which the patient was known to be alive. 
Note: Survival calls will be made in the week following the date of DCO for the analysis. (These 
contacts should generally occur within 7 days of the DCO.) If patients are confirmed to be alive 
or if the death date is after the DCO date, these patients will be censored at the date of DCO. 
Death dates may be found by checking publicly available death registries.
Proportion of patients alive at 24 months (OS24)
The proportion of patients alive at 24 months (ie, OS24) will be defined as the Kaplan-Meier 
estimate of OS at 24 months. In addition, the proportion of patients alive at 12 months (ie, OS12) 
will be presented. This will be defined as the Kaplan-Meier estimate of OS at 12 months.
Rate of complete response
The rate of CR (per RECIST 1.1 as assessed by BICR) is defined as the number (%) of patients 
with at least 1 visit response of CR, which is subsequently confirmed.  Data obtained up until 
progression, or the last evaluable assessment in the absence of progression, will be included in 
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the assessment of rate of CR. Patients who go off treatment without progression, receive a 
subsequent therapy, and then respond will not be included as responders in the rate of CR. 
Duration of response
DoR (per RECIST 1.1 as assessed by BICR) will be defined as the time from the date of first 
documented response (which is subsequently confirmed) until the first date of documented 
progression or death in the absence of disease progression (ie, date of PFS event or censoring –
date of first response+1). The end of response should coincide with the date of progression or 
death from any cause used for the RECIST 1.1 PFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing toward the 
first visit response of CR or PR that was subsequently confirmed. If a patient does not progress 
following a response, then his or her DoR will be censored at the PFS censoring time. DoR will 
not be defined for those patients who do not have documented confirmed response.
Disease control rate
DCR at 
 (per RECIST 1.1 as assessed by BICR) is defined as the percentage of patients 
who have a best objective response (BoR) of CR or PR in the first 
 (to allow for late 
assessment within the assessment window) or who have SD for at least 
 after 
randomization (to allow for an early assessment within the ±1 week assessment window). Data 
obtained up until progression, or the last evaluable assessment in the absence of progression, will 
be included in the assessment of DCR. Patients who go off treatment without progression, 
receive a subsequent therapy, and then respond will not be included as responders in the DCR.
Time to death or distant metastasis
TTDM will be defined as the time from the date of randomization until the first date of distant 
metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any NL 
that is outside of the radiation field according to RECIST 1.1 or proven by biopsy. Patients who 
have not developed distant metastasis or died at the time of analysis will be censored at the time 
of the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the 
patient has distant metastasis or dies after 2 or more missed visits, the patient will be censored at 
the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the patient 
has no evaluable visits or does not have baseline data, he/she will be censored at Day 1 unless 
they die within 2 visits of baseline.
 will be defined as the
 
will be 
recorded by the Investigator in the eCRF and defined according to local standard clinical practice 
and may involve any of the following: 
 
. The site will be asked whether the patient has had a 
 on a 
regular basis (q12w ±1 week) following 
 used for the 
 
 and the status recorded. Patients alive and for whom a 
 
 has not been observed should be censored at the last time known to be alive and 
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without 
, that is, censored at the latest of the 
 
assessment date if the patient has not had a 
. 
9.4.1.2
Calculation or derivation of safety variables
Adverse events
Data from all cycles of randomized treatment will be combined in the presentation of safety data. 
AEs (both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred term 
and CTCAE grade) will be listed individually by patient. 
Any AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs. Any AE occurring within 90 days of discontinuation of 
IP may be included in the AE summaries, but the majority of the AE summaries will omit the 
AEs observed after a patient has received further therapy for cancer. Further details will be 
provided in the Statistical Analysis Plan (SAP). Any AE that occurs after a patient has received 
further therapy for cancer (following discontinuation of IP) will be flagged in the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced. These events will not be included in AE summaries.
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca/MedImmune medically qualified expert 
will review the list of AEs that were not reported as SAEs and AEs leading to discontinuation. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as such 
in the CSR. A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. Examples of these are marked hematological and other laboratory 
abnormalities and certain events that lead to intervention (other than those already classified as 
serious) or significant additional treatment.
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of IP. 
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula.
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – Albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will include only evaluable patients, in other 
words, those who had sufficient data to have the possibility of an abnormality. 
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For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded.
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable, the 
patient need only have 1 post dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.4.1.3
Calculation or derivation of patient-reported outcome variables – EORTC 
QLQ-C30 and QLQ-LC13
Symptoms and overall quality of life will be assessed using the PRO questionnaires, EORTC 
QLQ-C30 and QLQ-LC13 (secondary endpoints). All questionnaires will be scored according to 
published guidelines or the developer’s guidelines, if published guidelines are not available. All 
PRO analyses will be based on the FAS. The clinical meaningfulness threshold of the PRO 
analyses described below will be provided in the SAP.
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a global measure of health status. The QLQ-LC13 is a lung cancer specific module 
from the EORTC for lung cancer comprising 13 questions to assess lung cancer symptoms 
(cough, hemoptysis, dyspnea, and site-specific pain), treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy, and alopecia), and pain medication. With the exception of a 
multi-item scale for dyspnea, all are single items. The dyspnea scale will only be used if all 
3 items have been scored; otherwise, the items are treated as single-item measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom 
scales/symptom items, the functional scales and the global health status scale in the QLQ-C30 
and for each of the symptom scales/items in the QLQ-LC13 according to the EORTC QLQ-C30 
Scoring Manual and EORTC QLQ-LC13 instructions.
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom severity.
Changes in score compared with baseline will be evaluated. For each subscale, if <50% of the 
subscale items are missing, then the subscale score will be divided by the number of non-missing 
items and multiplied by the total number of items on the subscales (Fayers et al 2001). If at least 
50% of the items are missing, then that subscale will be treated as missing. Missing single items 
are treated as missing. The reason for any missing questionnaire will be identified and recorded. 
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Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated. A minimum clinically meaningful 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-C30 and the QLQ-LC13 (Osoba et al 1998). For example, a clinically meaningful 
deterioration or worsening in chest pain (as assessed by QLQ-LC13) is defined as an increase in 
the score from baseline of ≥10. A clinically meaningful improvement in fatigue (as assessed by 
QLQ-C30) is defined as a decrease in the score from baseline of ≥10. At each post-baseline 
assessment, change in symptoms/functioning from baseline will be categorized as improved, 
stable or worsening as shown in Table 12.
Table 12
Visit responses for symptoms and HRQoL
Score
Change from baseline
Visit response
QLQ-C30/QLQ-LC13 Symptom 
scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
QLQ-C30 functional scales and 
global health status/QoL
≥+10
Improved
≤-10
Worsened
Otherwise
Stable
EORTC  European Organisation for Research and Treatment of Cancer; QLQ C30  30 item core quality of life 
questionnaire; QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; QoL Quality of life.
Time to symptom deterioration (QLQ-C30 and QLQ-LC13)
For each of the symptoms scales/items in the EORTC QLQ-C30 and QLQ-LC13, time to 
symptom deterioration will be defined as the time from the date of randomization until the date 
of the first clinically meaningful symptom deterioration (an increase in the score from baseline of 
≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically 
meaningful symptom deterioration, regardless of whether the patient withdraws from IP or 
receives another anticancer therapy prior to symptom deterioration. Death will be included as an 
event only if the death occurs within 2 visits of the last PRO assessment where the symptom 
change could be evaluated. 
Patients whose symptoms (as measured by EORTC QLQ-C30 and QLQ-LC13) have not shown 
a clinically meaningful deterioration and who are alive at the time of the analysis will be 
censored at the time of their last PRO assessment where the symptom could be evaluated. Also, 
if symptoms deteriorate after 2 or more missed PRO assessment visits or the patient dies after 
2 or more missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated. If a patient has no evaluable visits or does 
not have baseline data, he/she will be censored at Day 1.
The population for the analysis of time to symptom deterioration will include a subset of the FAS 
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Time to HRQoL/function deterioration (QLQ-C30) 
For HRQoL and function (as measured by EORTC QLQ-C30), time to deterioration will be 
defined as the time from the date of randomization until the date of the first clinically meaningful 
deterioration (a decrease in the score from baseline of ≥10) that is confirmed at a subsequent visit 
or death (by any cause) in the absence of a clinically meaningful deterioration, regardless of 
whether the patient withdraws from IP or receives another anticancer therapy prior to 
HRQoL/function deterioration. Death will be included as an event only if the death occurs within 
2 visits of the last PRO assessment where the HRQoL/function change could be evaluated. 
Patients whose HRQoL or function have not shown a clinically meaningful deterioration and 
who are alive at the time of the analysis will be censored at the time of their last PRO assessment 
where the HRQoL/function could be evaluated. Also, if HRQoL deteriorates after 2 or more 
missed PRO assessment visits or the patient dies after 2 or more missed PRO assessment visits, 
the patient will be censored at the time of the last PRO assessment where HRQoL/function could 
be evaluated. If a patient has no evaluable visits or does not have baseline data, he/she will be 
censored at Day 1.
The population for the analysis of time to QoL/function deterioration will include a subset of the 
ITT population who have baseline scores of ≥10.
Symptom improvement rate (QLQ-C30 and QLQ-LC13)
The symptom improvement rate will be defined as the number (%) of patients with 2 consecutive 
assessments at least 14 days apart that show a clinically meaningful improvement (a decrease in 
score of ≥10) in that symptom from baseline.
The denominator will consist of a subset of the ITT population who have a baseline symptom 
score of >10.
HRQoL/function improvement rate (QLQ-C30)
The HRQoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful improvement 
(an increase in score of ≥10) in that scale from baseline.
The denominator will consist of a subset of the ITT population who have a baseline 
QoL/function score of ≤90.
9.4.1.4
Calculation or derivation of patient-reported outcome variables–PGIS
PGIS data will be presented using summaries and descriptive statistics. Further details will be 
provided in the SAP. 
9.4.1.5
Calculation or derivation of patient-reported health state utility (EQ-5D-5L)
The health state utility will be assessed using the EQ-5D-5L (exploratory). The index comprises 
5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression; see Section 8.1.3.3). For each dimension, respondents select which statement 
best describes their health on that day from a possible 5 options of increasing levels of severity 

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100 (170)
(no problems, slight problems, moderate problems, severe problems, and extreme problems). A 
unique EQ-5D health state is referred to by a 5-digit code, allowing for a total of 3125 health 
states. For example, state 11111 indicates no problems on any of the 5 dimensions. These data 
will be converted into a weighted health state index by applying scores from EQ-5D value sets 
elicited from general population samples (the base case will be the United Kingdom valuation 
set, with other country value sets applied in scenario analyses). Where value sets are not 
available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied (Oemar and Janssen 2013). In 
addition to the descriptive system, respondents also assess their health on the day of assessment 
on a visual analog scale, ranging from 0 (worst imaginable health) to 100 (best imaginable 
health). This score is reported separately. 
9.4.2
Efficacy analyses
Efficacy data will be summarized and analyzed using the FAS. All outputs will be summarized 
by treatment arm for all randomized patients (Intent-to-Treat population).
The following table (Table 13) details which endpoints are to be subjected to formal statistical 
analysis, together with pre-planned sensitivity analyses, making it clear which analysis is 
regarded as primary for that endpoint.
Table 13
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints analyzed
Notes
Progression-free survival
Primary analysis using stratified log-rank test using BICR 
assessments (RECIST 1.1)
Sensitivity analyses using BICR assessments (RECIST 1.1)
1) Interval censored analysis – evaluation time bias
2) Analysis using alternative censoring rules – attrition bias
 stratified log-rank test using site Investigator 
assessments (RECIST 1.1) –
Objective response rate
Primary analysis using CMH test, stratified by age 
 
) and stage 
Sensitivity analysis using a CMH test repeated using the site 
Investigator data based on RECIST 1.1
As a sensitivity analysis the ORR analyzed using logistic regression 
adjusting for the same factors as for PFS
Overall survival
Stratified log-rank test
Sensitivity analysis using a Kaplan-Meier plot of time to censoring 
where the censoring indicator of the primary analysis is reversed –
attrition bias
Proportion of patients alive at 
24 months
Kaplan-Meier estimates of survival at 24 months and p-value 
(following the method described by Klein et al 2007)
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Endpoints analyzed
Notes
Rate of CR
Analysis using CMH test using BICR assessment RECIST 1.1 data
Sensitivity analysis using the CMH test using site Investigator tumor 
data (RECIST 1.1)
Duration of response
Kaplan-Meier estimates
Disease control rate
Summarized by descriptive statistics
Time to death or distant 
metastasis
Stratified log-rank test using BICR data (RECIST 1.1)
 
 
 in key 
symptoms (EORTC QLQ-C30 
and QLQ-LC13)
Mixed model repeated measures analysis
HRQoL/Function 
improvement rate (EORTC 
QLQ-C30 endpoints)
Summarized by descriptive statistics
Symptom improvement rate 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Logistic regression
Time to HRQoL/Function 
deterioration (EORTC 
QLQ-C30 endpoints)
Stratified log-rank test
Time to symptom deterioration 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Stratified log-rank test
BICR Blinded Independent Central Review; CMH Cochran-Mantel-Haenszel; EORTC European Organisation for 
Research and Treatment of Cancer; HRQoL  Health-related quality of life; ORR Objective response rate; 
PFS Progression-free survival; PFS2  Time from randomization to second progression; QLQ-C30 v3 30-item 
Core Quality of Life Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality of Life 
Questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1.
9.4.2.1
Primary endpoint: Progression-free survival
PFS based on the BICR data will be analyzed using a stratified log-rank test adjusting for by age 
) and stage
 The p-value will be obtained from the stratified 
log-rank test.
The HR and its CI can be estimated from the Cox proportional hazards model (Cox 1972). 
Kaplan Meier plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each treatment.
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Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analyzed. For patients whose death was treated as PFS event, the date of death will be used to 
derive the PFS time used in the analysis. This approach has been shown to be robust to even 
highly asymmetric assessment schedules (Sun and Chen 2010).
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following 2, or more, non-evaluable tumor assessments will be 
included. In addition, patients who take subsequent therapy prior to progression or death will be 
censored at their last evaluable assessment prior to taking the subsequent therapy. 
Ascertainment bias will be assessed by analyzing site Investigator data. The stratified log-rank 
test will be repeated on the programmatically derived PFS using the site Investigator data based 
upon RECIST. 
If there is an important discrepancy between the primary analysis using the BICR and this 
sensitivity analysis using site Investigator data assessments, then the proportion of patients with 
site but no central progression will be summarized; such patients have the potential to introduce 
bias in the central review due to informative censoring. An approach that imputes an event at the 
next visit in the central review analysis may help inform the most likely HR value (Fleischer et al 
2011), but only if an important discrepancy exists.
Subgroup analyses will be conducted comparing PFS between treatments in the following 
subgroups of the FAS (but not limited to):
!
Planned chemotherapy treatment regimen (identified prior to randomization)
!
Planned radiation therapy (intensity-modulated radiation therapy vs 3-dimensional 
conformal radiation therapy) (identified prior to randomization)
!
Region
!
Race/ethnicity
!
Sex
!
Age
!
Smoking status
!
Stage 
!
Histology
!
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!
!
Planning target volume (PTV)
Other baseline variables may also be assessed if there is clinical justification or an imbalance is 
observed between the treatment arms. The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic factors.
For each subgroup, the HR (for the treatment comparisons of interest) and 95% CI will be 
calculated from a Cox proportional hazards model that contains treatment. These will be 
presented on a forest plot including the HR and 95% CI.
No adjustment to the significance level for sensitivity or subgroup analyses will be made, since 
all these analyses will be considered supportive of the primary analysis of PFS.
Unless there is a marked difference between the results of the statistical analyses of the PFS from 
the BICR tumor data and that of the site Investigator, the subgroup analyses will only be 
performed upon the PFS endpoint using BICR data.
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate.
Interactions between treatment and stratification factor will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985).
If there are too few events available for a meaningful analysis of a particular subgroup (it is not 
considered appropriate to present analyses where there are less than 10 events in a subgroup), the 
relationship between that subgroup and PFS will not be formally analyzed. In this case, only 
descriptive summaries will be provided.
Censoring rules will be provided in the SAP.
9.4.2.2
Objective response rate
The ORR will be based on BICR data. The ORR will be compared between treatment arms using 
a Cochran-Mantel-Haenszel (CMH) test, stratified by age 
 and stage 
 
. As a sensitivity analysis, the ORR will be analyzed using logistic regression adjusting 
for the same factors as for PFS.
The analysis of ORR using a CMH test will be repeated using the site Investigator data based on 
RECIST 1.1 as a sensitivity analysis to confirm the results of the primary analysis.
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). Overall visit response data will be listed and summarized over time for all 
patients (ie, the FAS). For each treatment arm, the BoR will be summarized by n (%) for each 
category (CR, PR, NED, SD, PD, and NE). No formal statistical analyses are planned for BoR.
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9.4.2.3
Overall survival
OS will be analyzed using a stratified log-rank test, using the same methodology as described for 
the primary PFS endpoint. The effect of treatment will be estimated by the HR together with its 
corresponding 95% CI. Kaplan Meier plots of OS will be presented by treatment arm. 
Summaries of the number and percentage of patients who have died, those still in survival 
follow-up, those lost to follow-up, and those who have withdrawn consent will be provided along 
with the median OS for each treatment. Subgroup analyses maybe performed if there are a 
sufficient number of OS events.
9.4.2.4
Proportion of patients alive at 24 months
The proportion of patients alive at 24 months (ie, OS24) will be summarized (using the 
Kaplan-Meier curve) and presented by treatment arm. For each treatment arm, the survival rate at 
24 months based on Kaplan-Meier method will be presented, along with its 95% CI. The 
computation of the CI will be based on a log(-log(.)) transformation. It will be compared 
between treatments by using the Kaplan-Meier estimator of survival at 24 months for each 
treatment to obtain the HR. The HR and CI will be presented.
For the comparison between treatments, the test will be based on the method described in Klein 
2007 (Klein et al 2007). The test statistic and its variance estimate are as follows:
!
test statistic = 
)
(
ˆ
ln
)
(
ˆ
ln
ln
2
1
t
S
t
S
!
variance estimate = 
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t
#
#
∃
where 
%
&
∀
∋
t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2
#
is the variance derived from Greenwood’s formula S(t) and can be 
estimated from standard software packages, where di and ni refer to the number of deaths and 
patients at risk for each risk set.
!
The z-statistic is then calculated as:  
estimate
variance
statistic
test 
For the stratified analysis, the test statistic and its variance estimate in each strata will be 
combined by weighting inversely proportionately according to each within stratum variance 
(Whitehead and Whitehead 1991). A Z-test will be performed, and the p-value from the test will 
be presented.
9.4.2.5
Rate of complete response
Rate of CR will be analyzed in the same way as for ORR.

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9.4.2.6
Duration of response
Kaplan-Meier estimates will be provided for the DoR in responding patients (ie, median DoR 
and 95% CIs) by treatment arm, including the associated Kaplan-Meier curves (without any 
formal comparison of treatment arms or p-value attached).
9.4.2.7
Disease control rate
DCR will be summarized using descriptive statistics by treatment arm.
9.4.2.8
Time to death or distant metastasis
TTDM will be analyzed using identical methods as outlined for the analysis of PFS and adjusting 
for the same set of covariates, but no subgroup analysis will be performed. Medians and 
Kaplan-Meier plots will be presented to support the analysis. 
9.4.2.10
Patient-reported outcomes: EORTC QLQ-C30 and QLQ-LC13
Five symptoms have been identified as primary: 
!
Dyspnea: multi-item scale based on 3 questions (“Were you short of breath when you 
rested; walked; climbed stairs” – QLQ-LC13),
!
Cough: 1 item (“How much did you cough?” – QLQ-LC13),
!
Chest pain: 1 item (“Have you had pain in your chest” – QLQ-LC13).
!
Fatigue: multi-item based on 3 questions (“Did you need rest; Have you felt weak; 
Were you tired” – QLQ-C30)
!
Appetite loss: 1 item (“Have you lacked appetite” – QLQ-C30)
The physical functioning and overall health status domains of the EORTC CT30 are furthermore 
pre-specified endpoints of interest.
Mixed models repeated measures (MMRM) analysis
Change from baseline in dyspnea, cough, and chest pain scores as assessed by the EORTC 
QLQ-LC13 and fatigue and appetite loss as assessed by the EORTC QLQ-C30 will be the 
primary analysis and assessment of PRO outcome measures. The analysis will be performed 
using a linear mixed model for repeated measures (MMRM) analysis of change from baseline in 
the scores for each assessment timepoint and the Bonferroni-Holm procedure for adjusting the 
significance level will be used to aid interpretation. Therefore, the 5 endpoints will be tested at a 
1% significance level.
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Time to deterioration
Time to symptom and function/HRQoL deterioration will be analyzed for each of the symptom 
scales/items, function scales, and global health status/QoL in EORTC QLQ-C30 and 
QLQ-LC13. This will be achieved by comparing between treatment arms using a stratified 
log-rank test as described for the primary analysis of PFS. The HR and 95% CI for each 
scale/item will be presented graphically on a forest plot. 
For each of the symptom scales/items, functional scales, and global health status/QoL, time to
deterioration will be presented using a Kaplan-Meier plot. Summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death and the median 
time to deterioration will also be provided for each treatment arm.
Symptom and function/HRQoL improvement rate
A summary of the symptom improvement rate for all symptom scales/items in EORTC 
QLQ-C30 and QLQ-LC13 will be produced. Similarly, a summary of function/HRQoL 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced. 
Symptom improvement rates will be analyzed by comparing between treatment arms using a 
logistic regression model. The odds ratio and 95% CI for each scale/item will be presented 
graphically on a forest plot. If there are very few responses in 1 treatment arm, a Fisher’s exact 
test will be considered.
Change from baseline
Summaries of original and change from baseline values of each symptom scale/item, the global 
HRQoL score, and each functional domain will be reported by assessment timepoint for each 
treatment arm. Graphical presentations may also be produced as appropriate. Summaries of the 
number and percentage of patients in each response category at each assessment timepoint for 
each ordinal item (in terms of the proportion of patients in the categories of improvement, stable, 
and deterioration as defined in Table 12) will also be produced for each treatment arm.
EuroQol-5-Dimension 5-Level questionnaire
Descriptive statistics will be reported for the health state domain (eg, proportion in each domain) 
and the visual analog scale by visit, as well as the change in the visual analog scale value and the 
derived utility index value from baseline. To support future economic evaluations, additional 
appropriate analyses may be undertaken, for example, mean health state utility pre- and 
post-treatment and pre- and post-progression.
9.4.2.11
Health care resource use
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalization, outpatient, day case), reason, length of stay by ward type (including intensive 
care unit), and procedures and tests may be undertaken to examine the impact of disease and 
treatment on resource use to primarily support the economic evaluation of SoC CRT given 

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concurrently with durvalumab. This would include providing descriptive statistics as appropriate, 
including means, median, and ranges.
9.4.3
Safety analyses
Safety and tolerability data will be presented by treatment arm using the safety analysis set.
Data from all cycles of treatment will be combined in the presentation of safety data. AEs (both 
in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. 
The number of patients experiencing each AE will be summarized by treatment arm and CTCAE 
grade. Additionally, data presentations of the rate of AEs per person-years at risk may be 
produced. 
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, urinalysis, vital signs, and ECGs. Exposure to CRT, durvalumab, and placebo will 
be summarized. Time on study and CRT/durvalumab/placebo dose interruptions will also be 
summarized. At the end of the study, appropriate summaries of all safety data will be produced, 
as defined in the SAP.
9.4.4
Durvalumab concentration data will be listed for each patient and each dosing day, and a 
summary will be provided for all evaluable patients. Data collected in this study may be utilized 
to perform population 
 analysis.
9.4.5
 analysis
 results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable 
. The 
 
titer and presence of neutralizing 
 will be reported for samples confirmed positive for the 
presence of 
 The effect of 
, pharmacodynamics, efficacy, and 
safety will be evaluated, if data allow.
9.4.6
 relationships
If the data are suitable, the relationship between durvalumab 
 
 may be investigated graphically or using appropriate data modeling approach.
9.4.7
Biomarker data
The relationship of 
 expression and, if appropriate, of exploratory biomarkers to clinical 
outcomes (including but not restricted to PFS) may be presented.
9.4.8
Methods for multiplicity control
The multiple testing procedure (Figure 2) will define which significance levels should be applied 
to the interpretation of the raw p-values for the primary endpoints of PFS and the key secondary 
endpoints, ORR, OS and OS24. The family-wise error rate is strongly controlled at 5% for these 
endpoints.
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The testing procedure is 
 The overall 5% type I error will be first assigned to the 
 is significant at 
or the 
, an 
alpha level of 
 will be allocated to the 
 will be 
allocated to the 
 analysis. If the 
, then the 
 alpha will be 
 endpoint. If the OS analysis is significant at either the IAs or the final 
analysis, then the available alpha for OS will be recycled to the OS24 endpoint. 
If the OS24 analysis is significant, then the available alpha for OS24 will be recycled to the ORR
endpoint. This detail is not shown in Figure 2 and will be included in study Statistical Analysis 
Plan.
Formal statistical testing of ORR will occur when PFS is statistically significant. If additional 
alpha is recycled to ORR at later timepoint, the formal testing of ORR will be based on the data 
at the time when PFS is statistically significant.
Formal statistical testing of OS24 will occur after 24 month of LSI and when OS is statistically 
significant.
For the PFS endpoint, 
, and the alpha level will be controlled at the 
 
 by using the Lan-DeMets (Lan and DeMets 1983) spending 
function that approximates an O’Brien Fleming approach. For the OS endpoint, 
 
, and the alpha level will be controlled 
 by 
using the Lan-DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach. The O’Brien Fleming boundaries for the 
 will be 
adjusted depending on the alpha used for the endpoint.
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Figure 2
9.5
Interim analyses
Interim monitoring for safety will be conducted by the IDMC. Details of the plan and 
communication process will be provided in the SAP and the IDMC charter.
The alpha level allocated to PFS will be controlled at the interim and primary timepoints by 
using the Lan-DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach, where the significance level applied at the interim depends upon the 
proportion of information available. With the alpha level of 5%, if 
 of PFS events required at 
the time of the primary PFS analysis are available at the time of the interim (ie,
 
events have occurred), the 2-sided significance level to be applied for the PFS IA would be 
 and the 2-sided significance level to be applied for the primary PFS analysis would be 
.
In addition, 
 will be performed 
. The 
 
 when approximately 
 of the final number of OS events is expected to be reached 
(approximately 
 OS events). The 
 is when 
 of the final number of 
events is expected to be reached (approximately 
 OS events). It is expected that 
recruitment will have completed prior to the results of the IAs being available.
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The alpha level allocated to OS will depend on the results of the PFS and ORR analysis (see 
Section 9.4.8). It will be controlled at the interim and primary timepoint by using the Lan 
DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien Fleming 
approach, where the significance level applied at the IA depends upon the proportion of 
information available. For example, if the alpha level is 
and if 
 and 
 of OS events 
required at the time of the 
 analysis are available at the time of the IA (ie,
 
and 
events have occurred), the 2-sided significance level to be applied for the 
 
would be 
and 
 respectively, and the 2-sided significance level to be applied for the 
 analysis would be 
.
9.5.1
Independent Data Monitoring Committee
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
A data monitoring committee will be utilized for this study. Section A 5 provides more details on 
the rationale for and the remit of the committee.
An IDMC composed of independent experts will be convened to confirm the safety and 
tolerability of the proposed dose and schedule of durvalumab + SoC CRT. The first safety review 
will take place when the first
 
 The second safety review will take place when 
the first
 
 Safety reviews will be carried out by the IDMC in an unblinded 
manner. After review of the unblinded data, the IDMC will make a recommendation on whether 
the study should continue recruitment as planned or hold recruitment.
An additional safety review for 
 patients will take place when the first patients in 
 have completed SoC CRT and had 
 of follow-up. This review will be carried out 
by the IDMC in an unblinded manner. After review of the unblinded data, the IDMC will make a 
recommendation on whether the study should continue recruitment as planned or hold 
recruitment in 
The IDMC will also meet approximately every 
 thereafter to continue safety 
monitoring. 
In addition:
!
The IDMC will review the efficacy data for the primary PFS IA and if PFS is positive, 
ORR analysis ORR, CR, and DCR.
!
The IDMC will review the efficacy data for the 
, at the time of the 
 
, else when approximately 
 have 
been observed.
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!
The IDMC will review the efficacy data when approximately 
 OS events have 
occurred at the time of the 
, if 
.
Full details of the IDMC procedures, processes, and IAs can be found in the IDMC Charter.
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10.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
!
Applicable ICH Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.

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A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorised 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained before
the patient was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of the 
study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded 
from other aspects of the study.
If a patients partner becomes pregnant during or within 90 days after the study, the partner is 
asked to sign the “Adult Study Informed Consent Form for Pregnant Partners of Study Patients” 
and provide information about the pregnancy accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorised designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. The patient will give a separate agreement to allow any remaining specimens to be used 
for exploratory research. Patients who decline to participate in this optional research will indicate 
this in the ICF. If a patient withdraws consent to the use of donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples already have been 
analysed at the time of the request, AstraZeneca will not be obliged to destroy the results of this 
research.
A 4
Data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, their 
general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.

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Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s identity 
and might also have access to his or her genetic data. Also, regulatory authorities may require 
access to the relevant files. Even so, the patient’s medical information and the genetic files 
would remain physically separate.
Each patient will be assigned a unique identifier by the sponsor. Any patient records or data sets 
transferred to the sponsor will contain only the identifier; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on other 
websites according to the regulations of the countries in which the main study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 

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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified copies).
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.

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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a patient or clinical 
study patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.

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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B 6
CTCAE grade
The grading scales found in the revised National Cancer Institute CTCAE latest version will be 
utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B, B 2. An AE of severe intensity 
need not necessarily be considered serious. For example, nausea that persists for several hours 
may be considered severe nausea, but not a SAE unless it meets the criteria shown in 
Appendix B, B 2. On the other hand, a stroke that results in only a limited degree of disability 
may be considered a mild stroke but would be a SAE when it satisfies the criteria shown in 
Appendix B, B 2.
B 7
A guide to interpreting the causality question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.

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!
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant or 
has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.

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Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the drug
!
Did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given 
to the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed
!
Wrong participant received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of human biological samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the centre until shipment or disposal (where 
appropriate).
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring 
of study sites, auditing or process checks, and contractual requirements of external laboratory 
providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples have already been analyzed,
AstraZeneca is not obliged to destroy the results of this research.
The Investigator:
!
Ensures that AstraZeneca is immediately notified of the patient’s withdrawal of 
informed consent to the use of donated samples
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are immediately informed about the 
withdrawn consent immediately and that samples are disposed of or destroyed, the 
action documented, and the site is informed
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and the site is informed.

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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:
!
Are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
Are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient
!
Temperature in IATA 650 compliant packaging
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.ht
m)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which
require that they are also packed and transported in a safe and appropriate way to
contain any risk of infection or contamination by using approved couriers and
packaging/containment materials at all times. The IATA 650 biological sample

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containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix D
D 1
Use/analysis of 
 may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a 
 will be collected for 
 analysis from 
consenting patients.
AstraZeneca intends to collect, analyse, and store 
 for 
 research to explore how 
 may affect clinical parameters, risk and prognosis of diseases, and the 
response to medications. 
 research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. 
In addition, collection of 
 samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical studies and, 
possibly, to 
 guided treatment strategies.
 research may consist of the analysis of the structure of the patient´s 
 ie, the 
 
. 
The results of 
 analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The sponsor will store the 
 samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on durvalumab continues but no longer than 
15 years or other period as per local requirements.
D 2
 research plan and procedures
Selection of 
 research population
Study selection record
All patients will be asked to participate in this 
 research. Participation is voluntary and if a 
patient declines to participate there will be no penalty or loss of benefit. The patient will not be 
excluded from any aspect of the main study.
Inclusion criteria
!
For inclusion in this 
 research, patients must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent 
for the 
 sampling and analyses.
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Exclusion criteria
Exclusion from this
 research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous 
!
 in 120 days of 
 sample collection
Withdrawal of consent for 
 research:  
Patients may withdraw from this 
 research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for 
 research
The 
 sample for 
 research will be collected from the patients 
 at the 
 
. Although 
, early sample collection is preferred to avoid introducing 
bias through excluding patients who may withdraw due to an adverse event (AE), such patients 
would be important to include in any genetic analysis. If for any reason the sample is not drawn 
at the 
, it may be taken at 
. Only one sample 
should be collected 
 for 
 during the study. Samples will be collected, labelled, 
stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for 
analysis are important to 
maintain patient confidentiality. Samples will be stored for a maximum of 
, from the 
date of last patient last visit, after which they will be destroyed. 
 is a finite resource that is 
used up during analyses. Samples will be stored and used until no further analyses are possible or 
the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of 
 
 replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample and 
corresponding data at the AstraZeneca 
 laboratories, or at the designated organisation. 
No personal details identifying the individual will be available to any person (AstraZeneca 
employee or designated organisations working with the 
The link between the patient enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant 
 for 
analysis, facilitate correlation of 
 results with 
data, allow regulatory audit, and 
permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
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Informed consent
The 
 component of this study is optional and the patient may participate in other 
components of the main study without participating in the 
 component. To participate in 
the 
 component of the study the patient must sign and date both the consent form for the 
main study and the 
 component of the study. Copies of both signed and dated consent 
forms must be given to the patient and the original filed at the study centre. The Principal
Investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely withdrawal from the 
 aspect of the study at any time.
Patient data protection
AstraZeneca will not provide individual 
 results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent 
 data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might see 
both the 
 data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s identity 
and also have access to his or her 
 data. In addition, Regulatory authorities may require 
access to the relevant files, though the patient’s medical information and the genetic files would 
remain physically separate.
Data management
Any 
data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as 
 
 from 
 of individuals with a 
 from this 
 research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease. The researchers can only 
use this information for health related research purposes. Researchers may see summary results 
but they will not be able to see individual patient data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the 
 data in a 
suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the 
 research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.
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Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law
E 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. Specific guidance on managing liver abnormalities can be found in the 
Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5.1).
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets potential 
Hy’s law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s law (HL) criteria are 
met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication  irrespective of an increase in alkaline phosphatase (ALP). 
Hy’s law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
E 3
Identification of potential Hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination:
!
ALT ≥ 3 × ULN

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!
AST ≥ 3 × ULN
!
TBL ≥ 2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Appendix E, 0 for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Appendix E, 0 for definition) 
by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s law criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s law criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. Subsequent to this 
contact the Investigator will:

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!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 
 after the biochemistry abnormality was initially detected, the Study
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IP. The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:
!
Report an SAE (report term ‘Hy’s law’) according to AstraZeneca standard processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
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If there is an unavoidable delay of over 
 in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
E 6
Actions required when potential Hy’s law criteria are met before and 
after starting study treatment
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting Study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the last 
visit where PHL criteria were met.#
!
If there is no significant change, no action is required
!
If there is a significant change, notify the AstraZeneca representative, who will inform 
the central Study Team, then follow the subsequent process described in 
Appendix B, B 5.
!
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. 
The determination of whether there has been a significant change will be at the 
discretion of the Investigator, this may be in consultation with the Study Physician if 
there is any uncertainty.
E 7
Actions required for repeat episodes of potential Hy’s law
This section is applicable when a patient meets PHL criteria on study treatment, and has already 
met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
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Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix E, 0.
If No: Follow the process described in Appendix E, E 4.1.
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E, 0.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty.

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Appendix F
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009) for this study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this study. 
Additional special guidance is provided for evaluation of scans following a RECIST 1.1-defined 
PD scan using confirmation of radiologic progression criteria.
Definitions of measurable, non-measurable, target and non-target lesions
Only patients with measurable target disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been previously irradiated. 
Measurable:
A lesion, not previously irradiated per the protocol prior to randomization, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have 
short axis1 diameter of ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) and which is suitable for accurate repeated measurements.
Non-measurable:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).
!
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.
!
Brain metastasis
                                               
1 The short axis is defined as the longest axis perpendicular to long axis
2 Nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).

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Special cases:
!
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable.
!
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected as target lesions (TLs).
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative of 
all lesions involved suitable for accurate repeated measurement, should be identified as TLs at 
baseline. Lymph nodes, in any location, are collectively considered as a single organ, with a 
maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands) is considered as a 
single organ. Each segmented organ (eg, liver) or lobular organ (eg, lung) is considered as a 
single organ.
Prior irradiated lesions may be considered measurable and selected as TLs provided they fulfill 
the other criteria for measurability. Tumor lesions selected for screening biopsy should not be 
selected as TLs, unless imaging occurred at least 
 after biopsy, allowing time for 
healing.
Non-target lesions:
Additional measurable and non-measurable lesions (or sites of disease) not recorded as TL 
should be identified as Non-Target Lesion (NTL) at baseline.
Methods of assessment
The same method of assessment on the same imaging technique should be used to 
characterize each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 14, and those 
excluded from tumor assessments for this study are highlighted with the rationale provided.
Table 14
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18F-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging.
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CT and MRI
CT and MRI, each preferably with intravenous (IV) contrast, are generally considered to 
generate the best currently available and reproducible images for measurement of TL, 
assessment of NTL, and identification of any new lesions. 
It is recommended that CT examinations of the chest and abdomen (including the entire liver and 
both adrenal glands) will be used to assess tumor burden at baseline and follow-up visits. Any 
other areas of disease involvement should be additionally imaged based on the signs and 
symptoms of individual patients. In patients who are sensitive to IV CT contrast, a 
noncontrast- CT examination of the chest and an MRI with IV contrast of the abdomen is 
appropriate. In patients with severely compromised renal function a non-contrast CT 
examination of the chest and abdomen is appropriate. For brain lesion assessment, MRI with IV 
contrast is the preferred method over IV contrast enhanced CT. It is strongly recommended to 
maintain use of the same imaging modality (CT or MRI), acquisition protocol, facility and 
scanner across all imaging timepoints per patient.
Clinical examination 
Clinical examination of skin lesions or surface tumors (by visual inspection or manual palpation) 
will not be used for RECIST assessments. Tumors identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans.
X-ray
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence of 
new bone lesions. 
Ultrasound 
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible method, does not provide an accurate assessment of tumor size, and it is subjective 
and operator dependent. Tumors identified by ultrasound examination will need to be assessed 
by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.
Tumor markers 
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1.

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Cytology and histology 
Histology on tumor biopsy samples will not be used as part of the tumor response assessment as 
per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be used 
as part of the RECIST 1.1 tumor response assessments in this study. An effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be
considered to be disease progression due to new lesions or progression of NTLs, respectively.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
Xray- at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone 
lesions at follow-up visits. New lesions may be recorded in the event that positive hotspots 
appear on a bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hotspot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
X-ray) of the same anatomical region shall not be the only trigger for a progressive disease (PD) 
assessment at that timepoint.
FDG-PET scan
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET) 
scans may be used as a method for identifying new lesions, according to the following algorithm:  
New lesions will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake3 not 
present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI at 
the same follow-up visit. If there is no baseline or prior FDG-PET scan available, and no 
evidence of new lesions on CT/MRI scans, then follow-up CT/MRI assessments should be 
continued, scheduled as per protocol or clinical indicated, in order to verify new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan are 
of limited use in anatomically-based efficacy assessments, and it is therefore suggested that they 
should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed as part of a PET/CT examination is of identical diagnostic quality (with IV contrast) 
to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used for RECIST 
1.1 tumor assessments. Caution that this is not recommended because the PET portion of the CT 
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the 
surrounding tissue or liver is observed.

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introduces additional (PET) data that may bias an Investigator if it is not routinely or serially 
performed.
Tumor response evaluation 
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including liver and adrenal glands) must be used at each subsequent follow-up 
assessment. Additional imaging may be performed based on the signs and symptoms of the 
patient (eg, new lesions) at follow-up.
Baseline assessments should be performed no more than 28 days before start of study treatment, 
and ideally should be performed as close as possible to the start of IP. Efficacy by RECIST 1.1 
for all patients will be assessed according to the schedules of assessments. If an unscheduled 
assessment is performed, and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at their scheduled visits. 
For patients who discontinue IP due to toxicity in the absence of evidence of disease progression, 
tumor assessments should be continued according to the original imaging schedule. 
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
identified as TL at baseline. TLs should be selected on the basis of their size (longest diameter 
for non-nodal lesions or short axis for nodal lesions), but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as the 
baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be calculated 
and reported as the follow-up sum of diameters.
Special cases:
!
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 
!
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan.

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!
If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm. If a lesion appears in the same location on a subsequent scan, it will be recorded 
as a New Lesion.
!
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 
!
If two or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
!
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.
!
If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion. 
!
When a TL has had any intervention eg, definitive radiotherapy, embolization, 
surgery, etc. during the study, the size of the TL should still be provided where 
possible and the intervention recorded in the RECIST case report form. If a TL has 
been completely removed (surgery), the longest diameter should be recorded as 0 mm.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 15).

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Table 15
Evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum
if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (eg missing anatomy) or had a lesion intervention at 
this visit. Note: if the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a TL 
response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded by 
the Investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit (see Table 16).

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Table 16
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline. All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/non PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or partial 
response in TLs, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify 
for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of one 
or more new lesions is assessed as RECIST 1.1 progression. The finding of a new lesion should 
be unequivocal; ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor. If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should be 
continued until the previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.

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Symptomatic deterioration
Symptomatic deterioration is not a descriptor of a radiological response; it is a reason for 
stopping study therapy.
Patients with symptomatic deterioration requiring discontinuation of treatment without objective 
radiologic evidence of disease progression at that time should continue to undergo tumor 
assessments where clinically feasible.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 17.
Table 17
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no target and/or non-target lesions at baseline).
Tumor Assessment Criteria for Scans Following RECIST 1.1-defined PD
A follow-up scan is requested after an initial RECIST 1.1-defined PD, preferably at the next (and 
no later than the next) scheduled imaging visit, and no less than 
 after the prior 
assessment of PD. Additional guidance is provided below for evaluation of scans following a 
RECIST 1.1-defined PD scan, whereby the subsequent scan would be considered as PD if any 
the following criteria are met:
!
≥20% increase in the sum diameters of TLs compared with the nadir, with an absolute 
increase of at least 5 mm in sum of diameters compared to nadir (as per RECIST 1.1 
definition)
!
and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint (as per RECIST 1.1 definition)
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!
and/or significant progression (worsening) of pre-existing new lesions at the follow-up 
scan timepoint compared with the immediate prior timepoint
!
and/or additional (brand) new unequivocal lesions at the follow-up scan timepoint (as 
per RECIST 1.1 definition)
Central review
If specified, all images will be collected, quality checked, and stored centrally by an Imaging 
CRO appointed by AstraZeneca. Guidelines for image acquisition, anonymization, storage at the 
Investigative site as source data, and transfer to the imaging CRO will be provided in a separate 
document. A BICR of images will be performed at the discretion of AstraZeneca. Results of 
these independent reviews will not be communicated to Investigators, and results of Investigator 
RECIST assessments will not be shared with the central reviewers. The management of patients 
will be based in part upon the results of the RECIST 1.1 assessment conducted by the 
Investigator.
Further details of the BICR will be documented in the Independent Review Charter, (also 
referred to as ‘Imaging Charter’).
Specifications for anatomical imaging
These notes are recommendations for use in clinical studies. The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective of 
where the examination has been undertaken.
CT scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous throughout 
all the anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and reconstruction 
interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, abdomen 
and pelvis. Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients. Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up timepoints. This will enable better consistency not only of tumor 
measurements but also identification of new disease.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination. An adequate volume 
of a suitable contrast agent should be given so that the metastases are demonstrated to best effect 
and a consistent method is used on subsequent examinations for any given patient. It is very 

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important that the same technique be used at baseline and on follow- up examinations for a given 
patient. For patients who develop contraindications to contrast after baseline contrast CT is done, 
the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be 
performed should also be based on the tumor type, anatomic location of the disease and should 
be optimised to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. Care must be 
taken in measurement of TLs on a different modality and interpretation of non-target disease or 
new lesions, since the same lesion may appear to have a different size using a new modality. 
Oral contrast is recommended to help visualise and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the course 
of the study then the recommended methods are: CT thoracic (chest) examination without 
contrast and abdominal and pelvis MRI with contrast. If MRI cannot be performed then CT 
without IV contrast is an option for the thorax, abdomen, and pelvis examination. For brain 
imaging, MRI with IV contrast is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be performed 
at 5mm contiguous slice thickness and this guideline presumes a minimum 5 mm thickness in 
recommendations for measurable lesion definition. Exceptionally, particular institutions may 
perform medically acceptable scans at slice thicknesses greater than 5 mm. If this occurs, the 
minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
All window settings should be included in the assessment, particularly in the thorax where lung 
and soft tissue windows should be considered. When measuring lesions, the TL should be 
measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” images 
of the apparent lesion.
MRI scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality used 
at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis (and other anatomies eg neck) with T1 and T2 weighted imaging along with gadolinium-
enhanced imaging can be performed. The field of view, matrix, number of excitations, phase 
encoding steps, use of fat suppression and fast sequences should be optimised for the specific 
body part being imaged as well as the scanner utilised. CT of the chest is typically recommended 
over MRI due to significant motion artifacts (heart, major blood vessels, breathing) associated 
with MRI. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts and diseases. Ideally, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques if possible.
For these reasons, CT is the imaging modality of choice.

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References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix G
Radiation therapy: requirements and recommendations
G 1
Overview
Patients will be treated to a dose of 60 Gy in 30 fractions (2 Gy/fraction) using photons of 6 to 10 
MeV. Motion assessment is required, with motion management depending on the results of the 
motion assessment. Daily image-guided radiotherapy (IGRT) is required. Either intensity-
modulated radiation therapy (IMRT) or 3D-conformal radiotherapy (3D-CRT) is allowed, 
though IMRT is preferred (Chun et al. 2017).
G 2
Simulation
G 2.1
Immobilization
Some form of immobilization is required, with attention to patient comfort to prevent intra-
fraction motion.  Patients must be immobilized in a stable position using the participating 
institutions’s standard of practice.  A variety of immobilization systems may be used, including, 
but not limited to,  alpha-cradle, vacuum bag, thermoplastic molds, stereotactic frames and rigid 
pillows. 
G 2.2
Planning computed tomography (CT)
The treatment planning CT is required for defining target volumes and organs-at-risk (OARs). 
CT thickness should be a maximum of 0.3 cm, and the CT should be acquired with the patient in 
the same position and using the same immobilization device as will be used for treatment. 
All tissues receiving radiation should be included in the CT limits, extending from the bottom of 
the cricoid cartilage through the liver. The field of view must be large enough so that none of the 
patient’s anatomy along the path of the treatment beams is cut off.  The type of CT(s) acquired 
(free-breathing, breath-hold, etc.) will dictated by the motion assessment and motion 
management techniques chosen (see section H 2.3).
IV contrast during the planning CT is optional provided a diagnostic chest CT was done with 
contrast to delineate the major blood vessels. If not, IV contrast should be given during the 
planning CT unless medically-contraindicated. If contrast is used, the densities should be over-
ridden or the contrast scan must be registered to a non-contrast scan for treatment planning 
purposes.
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in the treatment 
position is encouraged for treatment planning. In the case where the PET/CT is obtained in the 
treatment position, the CT from this study may be used as the treatment planning CT scan.
G 2.3
Motion assessment and motion management
Motion assessment is required for this protocol to determine what motion management 
strategies are needed. For the purposes of this protocol, motion assessment is defined as a 
method to measure the end-to-end target motion under the influence of respiration, while motion 
management is defined as a method to minimize the influence of intra-fractional tumor motion on 
the delivered dose.

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Motion assessment
Motion assessment is required.  Four-dimensional CT (4DCT) simulation is the preferred 
method for motion assessment.  Fluoroscopy, using either a conventional simulator or the 
fluoroscopic imaging capabilities of the linear accelerator itseld, is also acceptable.
If the end-to-end target motion is & 10 mm, intra-fractional motion may be accounted for in 
the design of the target through the creation of an ITV (see section H 3.1).  Additional motion 
management approaches may still be used at the discretion of the participating institution.  
If the end-to-end target motion is > 10 mm, accounting for motion with an ITV alone is 
discouraged.  In such instances, it is recommended that more effective motion management 
strategies (examples given below) be employed.
Motion management
Acceptable forms of motion management include the following:
!
ITV defined using a 4DCT
!
ITV defined using fluoroscopy
!
Abdominal compression
!
Active breathing control (e.g. Elekta ABC device)
!
Active breath hold
!
Free-breathing gating (e.g. Varian RPM system)
!
Gated breath hold
!
Other, provided the participating institution can provide evidence that the motion 
management method employed reduces the effective motion of the target to & 10 mm.
G 3
Definition of target and organs-at-risk (OARs)
G 3.1
Target definitions
NOTE:  The current ICRU 62 guidelines suggest that contouring should proceed from GTV (
CTV ( ITV ( PTV.  Given the difficulty in visualizing microscopic disease when considering 
a moving tumor, this protocol will employ the more widely used approach of contouring from 
GTV ( ITV ( CTV ( PTV.
!
GTV: The GTV is all known gross disease including the primary tumor and involved 
lymph nodes (≥1 cm short axis diameter) as demonstrated on the treatment planning 
CT, and modified as deemed necessary based on PET and other imaging studies. 
!
ITV: The ITV is the GTV plus a margin to account for tumor motion.  For the 
preferred method of using a 4DCT, the ITV will be the union of the GTVs on all 
respiratory correlated images and/or the ITV may be contoured directly using 
maximum intensity projection (MIP) images.  Even if using a MIP, the delineated ITV 
will be compared with the actual position of the GTV on each of the respiratory 

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correlated CTs and modified, if necessary, to encompass the extent of motion of the 
GTV.  If fluoroscopy is used for motion assessment, the ITV will be the GTV plus up 
to 10 mm of margin in any direction (anisotropic margins) encompassing tumor 
motion.  The ITV may also be modified as deemed necessary based on PET and other 
clinical studies that may better distinguish the true GTV from other near unit-density 
tissues. (If a breath-hold technique is used, ITV is the union of the GTVs on 3 breath 
hold scans).
!
CTV: The CTV accounts for subclinical involvement around the GTV. The CTV is 
the ITV plus a 5 – 10 mm margin for microscopic extensions of the tumor (CTV =
ITV + 5 to 10 mm) without extending into uninvolved organs such as the esophagus, 
heart, or bone.
!
PTV: The PTV is the CTV plus a margin to ensure that the prescribed dose is actually 
delivered to the CTV. This margin accounts for variations in treatment delivery, 
including variations in setup between treatments. The CTV is expanded isotropically 
by 5 mm to generate the PTV (PTV = CTV + 5 mm).  Note that this 5 mm margin 
assumes that daily IGRT is employed, a protocol requirement (see section H 6.1).
G 3.2
Target delineation
The simulation CT scan images will be used for target delineation and treatment planning. The 
proper lung window should be used for target delineation in the lung parenchyma, and proper 
soft tissue window should be used to delineate the nodal disease.
If a pre-treatment PET/CT and/or contrast CT images was performed, these should be fused with 
the simulation images to help with target delineation.  Table 18 provides additional guidance on 
target delineation based on the simulation images and motion management strategy.
Table 18
Summary of motion management options, scans for dose calculations, 
and target delineation
Motion management
Scans
Scan to be used for 
dose calculation
Images from which the 
target volume contours 
are to be generated
4DCT simulation with 
free breathing
1 free breathing scan, 
1 4D scan (10 imaging 
data sets)
Average of all phases
MIP or union of the 
GTVs on all phases
4DCT simulation with 
free breathing gating
1 free breathing scan, 
1 4D scan (10 imaging 
data sets)
Average of the beam-on 
phases (eg, 40%-60%)
Union of GTVs 
contoured at each 
breathing phase while 
the beam will be on 
4DCT simulation with 
breath hold (with or 
without ABC)
Repeat breath hold scan 
3 times to assess 
reproducibility of the 
breath hold
Select 1 scan for dose 
calculation
Union of GTVs 
contoured at each breath 
hold scan

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Table 18
Summary of motion management options, scans for dose calculations, 
and target delineation
Motion management
Scans
Scan to be used for 
dose calculation
Images from which the 
target volume contours 
are to be generated
Single-slice CT 
Simulation (4DCT not
available)
1 free breathing scan,
1 end-inhale scan at end
tidal volume,
1 end-exhale scan at end
tidal volume
Free-breathing scan 
used for dose 
calculation
Union of GTVs of end-
inhale and end-exhale 
volumes
G 3.3
OAR delineation
The simulation CT scan images will be used for OAR delineation.  The OARs to be contoured 
include the spinal canal, both right and left lungs, the heart, the esophagus, and the brachial 
plexus for upper lobe tumors,. The liver and kidneys will also be contoured if these OARs will 
be in the beam path.  
The spinal canal will be contoured based on the bony limits of the spinal canal (not the spinal 
cord). The spinal canal should be contoured starting from the top of C1 (or the first CT slice) 
down through the bottom of L2 (or the last CT slice). The neural foramina should not be 
included.
Both lungs should be contoured using pulmonary windows. The right and left lungs will be 
contoured separately, but will be considered as one structure for lung dosimetry.  All inflated and 
collapsed, fibrotic and emphysematic lungs should be contoured, small vessels extending  
beyond the hilar regions should be included.
The heart will be contoured along with the pericardial sac. The superior aspect (or base) will 
begin at the level of the inferior aspect of the pulmonary artery passing the midline and extend 
inferiorly to the apex of the heart. 
The esophagus should be contoured from the beginning at the level just below the cricoid to its 
entrance to the stomach at GE junction. The esophagus will be contoured using mediastinal 
window/level on CT to correspond to the mucosal, submucosa, and all muscular layers out to the 
fatty adventitia. 
For the brachial plexus, only the ipsilateral brachial plexus is required, and is only required for 
upper lobe tumors.  This will include the spinal nerves exiting the neural foramina from top of 
C5 to top of T2.
When the beam path is projected to pass through the liver, the entire liver should be contoured. 
The gallbladder should be excluded from the liver contour, and the inferior vena cava should be 
excluded when it is discrete from the liver.

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When the beam path is projected to pass through one or both of the kidneys, both kidneys should 
be contoured. The kidney contours should include both the renal cortex and renal pelvis.
Table 19 provides the nomenclature to be used for this protocol.
G 4
Definition of structures
Table 19
Structure names
Standard Name
Description
Validation
GTV
Primary tumor and involved nodes
Required
ITV
Primary tumor and involved nodes 
inclusive of tumor motion
Required
CTV_6000
ITV + 5 to 10 mm margin, excluding 
anatomic boundaries to tumor spread
Required
PTV_6000
CTV + 5 mm margin
Required
Spine_Canal
Spinal canal
Required
Lung_R
Right lung
Required
Lung_L
Left lung
Required
Lungs
(Lung_R + Lung_L) – GTV 
Required
Heart
Whole heart
Required
Esophagus
Esophagus
Required
BrachialPlexus
Brachial plexus
Required for upper lobe 
tumors
Liver
Whole liver
Required if within beam path
Kidney_R
Right kidney
Required if within beam path
Kidney_L
Left kidney
Required if within beam path
G 5
Compliance criteria
G 5.1
Target dose
Compliance criteria for dose to targets are shown in Table 20.
G 5.2
Missed treatment days/elapsed days
Missed treatments can be compensated for by delivering additional twice-daily fractions (within 
a minimum interfraction interval of 6 hours), by treating on Saturday or Sunday, or by adding 
fractions to the end of treatment.
Treatment breaks should be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Compliance criteria for treatment duration and treatment interruptions are 
shown in Table 20.

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Table 20
Target and treatment time compliance criteria
Metric
Per protocol
Variation acceptablea
PTV_6000 coverage
≥95% covered by 100% prescribed 
dose
≥95% covered by ≥95% prescribed 
dose
PTV_6000 hot spots
<110% of prescribed dose to no 
more than 0.03 cc inside PTV
≥110% but <115% of prescribed 
dose to no more than 0.03 cc inside 
PTV
PTV_6000 cold spots
&95% of prescribed dose to no 
more than 0.03 cc inside PTV
<95% but ≥93% of prescribed dose 
to no more than 0.03 cc inside PTV
Overall RT treatment 
time
& 42 days
43 - 56 days
RT treatment days 
interrupted (other than 
holidays)
0
≤5
a Values not meeting the Variation Acceptable limits will be classified as Deviation Unacceptable. 
G 5.3
Dose to OARs
Compliance criteria for OARs are shown in Table 21.
Table 21
Recommended dose acceptance criteria for OARs
Per protocol
Variation acceptable a
Lungs
V20 ≤ 35%
Mean lung dose ≤ 20 Gy
V5 ≤ 60%
V20 ≤ 37%
Mean lung dose ≤ 22 Gy
V5 ≤ 65%
Esophagus
Maximum dose: 66 Gy 
Maximum dose: 69 Gy 
Brachial plexus
V66 ≤ 0.5 cc
V69 ≤ 0.5 cc
Spine_Canal
V50 < 0.03 cc
V52 < 0.03 cc
Heart
V50 ≤ 25%
V45 ≤ 35%
V30 ≤ 50%
V50 ≤ 30%
V45 ≤ 40%
V30 ≤ 55%
aValues not meeting the Variation Acceptable limits will be classified as Deviation Unacceptable. 
G 6
Treatment delivery
G 6.1
Image-guided radiation therapy (IGRT)
Daily IGRT, consisting of images and appropriate image alignment software tool, is required for 
treatment on this protocol. Patients will be treated only on units with image-guidance 
capabilities. 

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Daily IGRT may be achieved using any one or more of the following techniques: 
!
Orthogonal kilovoltage (kV) images, e.g., ExacTrac, on-board imagers or similar systems
!
Linear-accelerator mounted kV and MV conebeam CT images 
!
Linear-accelerator mounted MV CT images (e.g., Tomotherapy) 
!
Linear-accelerator on-board MV portal imaging, though less desired than the above 
options.
G 7
RT quality assurance reviews 
G 7.1
Pre-treatment review
Radiation plans will be collected and subject to centralized review to assess compliance with the 
protocol requirements. Final radiation reports will also be collected.
G 8
References
Chun et al. 2017
Chun SG, Hu C, Choy H, Kiomaki RU, Timmerman RD, Schild SE, et al. Impact of intensity-
modulated radiation therapy technique for locally-advanced non-small-cell lung cancer: A 
secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol 
2017; 35(1):56-62.

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Appendix H
Patient-reported outcomes
Patient Reported Outcome Questionnaire was removed due to copyrights.

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Patient Reported Outcome Questionnaire was removed due to copyrights.

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Patient Reported Outcome Questionnaire was removed due to copyrights.

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Appendix I
Abbreviations
Abbreviation or 
special term
Explanation
4D CT
four-dimensional computed tomography
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCss
area under the concentration versus time curve at steady state
B7-H1
B7 homolog 1
BICR
Blinded Independent Central Review
BoR
best objective response
BP
blood pressure
cCRT
concurrent chemoradiation therapy
CCTG
Canadian Cancer Trials Group
CD
cluster of differentiation
CI
confidence interval
CL
creatinine clearance
Cmaxss
maximum drug concentration at steady state
CR
complete response
CRF
case report form
CRP
C reactive protein
CRT
chemoradiation therapy
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
cytotoxic T-lymphocyte antigen 4
CTV
clinical target volume
DCO
data cutoff
DCR
disease control rate 
DoR
duration of response
CCI
CCI

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Abbreviation or 
special term
Explanation
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOI
end of infusion
EORTC
European Organisation for Research and Treatment of Cancer
EQ 5D-5L
EuroQoL 5 dimension, 5-level health state utility index
FAS
full analysis set
FDA
Food and Drug Administration
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography/computed 
tomography
FFPE
formalin-fixed paraffin-embedded
GCP
Good Clinical Practice
GI
gastrointestinal
GTV
gross tumor volume
HBV
hepatitis B
HCV
hepatitis C
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFNγ
interferon gamma
IgG
immunoglobulin G
IGRT
image-guided radiation therapy
ILD
interstitial lung disease 
IMRT
intensity-modulated radiation therapy
CCI

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Abbreviation or 
special term
Explanation
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
imAE
immune-mediated adverse event
IP
investigational product
irAE
immune-related adverse event
IRB
Institutional Review Board
ITT
Intent-to-Treat
ITV
internal target volume
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LDH 
lactate dehydrogenase
LIMS
laboratory information management system
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MIP
maximum intensity projection
MLD
maximum lung dose
MRI
magnetic resonance imaging
NE
not evaluable
NED
no evidence of disease
NL
New Lesion
NSCLC
non-small cell lung cancer
NTL(s)
non-target lesion(s)
OAE
other significant adverse event
ORR
objective response rate
OS
overall survival
OS24
proportion of patients alive at 24 months from randomization
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
CCI

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Abbreviation or 
special term
Explanation
PGIS
Patients’ Global Impression of Severity
PR
partial response
PRO
patient-reported outcome
PS
performance status
PTV
planning target volume
QA
quality assurance
QLQ-C30
30-item core quality of life questionnaire
QLQ-LC13
13-item lung cancer quality of life questionnaire
QoL
quality of life
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBE
relative biological effectiveness
RECIST
Response Evaluation Criteria In Solid Tumors
ROI
region of interest
SAE
serious adverse event 
SAP
statistical analysis plan
SD
stable disease
SoA
schedule of activities
SoC
standard of care
T-cell
T lymphocyte
TCs
tumor cells
TL(s)
target lesion(s)
TMG
Toxicity Management Guidelines
TNF-α
tumor necrosis factor alpha
TTDM
time to death or distant metastasis
ULN
upper limit of normal
CCI
CCI
CCI
CCI

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Abbreviation or 
special term
Explanation
US
United States
WHO
World Health Organization
WT
body weight

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d933kc00001-csp-v4
Document Title:
D933KC00001 Clinical Study Protocol version 4
Document ID:
Doc ID-003750089
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
12-Mar-2020 15:52 UTC
Content Approval
12-Mar-2020 14:53 UTC
Content Approval
09-Mar-2020 21:36 UTC
Content Approval
09-Mar-2020 19:48 UTC
Qualified Person Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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